U.S. patent application number 16/618759 was filed with the patent office on 2020-05-14 for gastric residence systems with release rate-modulating films.
The applicant listed for this patent is Lyndra, Inc.. Invention is credited to David ALTREUTER, Andrew BELLINGER, Nupura BHISE, Bennett CARTER, Colin GARDNER, Rosemary KANASTY, Susan LOW, James WRIGHT, Jung Hoon YANG, Stephen ZALE.
Application Number | 20200146979 16/618759 |
Document ID | / |
Family ID | 64566367 |
Filed Date | 2020-05-14 |
View All Diagrams
United States Patent
Application |
20200146979 |
Kind Code |
A1 |
KANASTY; Rosemary ; et
al. |
May 14, 2020 |
GASTRIC RESIDENCE SYSTEMS WITH RELEASE RATE-MODULATING FILMS
Abstract
The invention provides gastric residence systems, or components
of gastric residence system such as segments or elongate members of
gastric residence systems, with release rate-modulating films and
methods for making and using such systems. The release
rate-modulating films provide good control over release of agents
(such as therapeutic, diagnostic, or nutritional agents) present in
the gastric residence system. The films also permit higher drug
loading in the gastric residence systems and components of gastric
residence systems while maintaining good control over release of
agents. Some embodiments of the films can provide resistance
against burst release of agent upon exposure to alcohol.
Inventors: |
KANASTY; Rosemary;
(Cambridge, MA) ; BHISE; Nupura; (Cambridge,
MA) ; ZALE; Stephen; (Hopkinton, MA) ; CARTER;
Bennett; (Stoughton, MA) ; YANG; Jung Hoon;
(Brookline, MA) ; BELLINGER; Andrew; (Wellesley,
MA) ; LOW; Susan; (Pepperell, MA) ; WRIGHT;
James; (Lexington, MA) ; ALTREUTER; David;
(Wayland, MA) ; GARDNER; Colin; (Concord,
MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Lyndra, Inc. |
Watertown |
MA |
US |
|
|
Family ID: |
64566367 |
Appl. No.: |
16/618759 |
Filed: |
June 8, 2018 |
PCT Filed: |
June 8, 2018 |
PCT NO: |
PCT/US18/36743 |
371 Date: |
December 2, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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|
62652128 |
Apr 3, 2018 |
|
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|
62566111 |
Sep 29, 2017 |
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62517732 |
Jun 9, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/65 20130101;
A61K 47/10 20130101; A61K 47/14 20130101; A61K 47/32 20130101; A61K
47/34 20130101; A61K 31/445 20130101; A61K 31/519 20130101; A61K
9/146 20130101; A61K 9/0065 20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 47/34 20060101 A61K047/34; A61K 47/10 20060101
A61K047/10; A61K 47/14 20060101 A61K047/14; A61K 31/445 20060101
A61K031/445; A61K 31/65 20060101 A61K031/65; A61K 9/14 20060101
A61K009/14 |
Claims
1. A gastric residence system comprising a therapeutically
effective amount of an agent or a pharmaceutically acceptable salt
thereof, wherein: the gastric residence system has a compacted
configuration and an uncompacted configuration, the gastric
residence system comprises a plurality of elongate members affixed
to a central elastomer, wherein at least one elongate member
comprises: a carrier polymer, the agent or the pharmaceutically
acceptable salt thereof, and a release-rate modulating polymer film
coated on the surface of the at least one elongate member; wherein
the gastric residence system is configured to release the agent or
the pharmaceutically acceptable salt thereof over a specified
gastric residence period.
2. The gastric residence system of claim 1, wherein the polymer
film comprises one or more of polycaprolactone (PCL), polyglycolic
acid (PGA), polylactic acid (PLA), polylactic-co-glycolic acid)
(PLGA), a polyhydroxyalkanoate (PHA), polyhydroxybutyrate (PHB),
polyhydroxyvalerate (PHV),
poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), polyethylene
adipate (PEA), polybutylene succinate (PBS), a polyester with one
or more aromatic groups in the main chain, polyethylene
terephthalate (PET), polybutylene terephthalate (PBT),
polytrimethylene terephthalate (PTT), polyethylene naphthalate
(PEN), block or random copolymers incorporating the monomer
constituents of any of the foregoing, copolymers of lactide and
caprolactone (poly-lactide-co-caprolactone; PLC), cellulose acetate
(CA), ethyl cellulose (EC), copolymers of acrylate and methacrylate
esters, Eudragit RS; or a mixture of two or more of the
foregoing.
3. The gastric residence system of claim 1, wherein the
release-rate modulating polymer film comprises polycaprolactone,
polydioxanone, polylactic acid or poly(lactic-co-glycolic
acid).
4. The gastric residence system of claim 1, in the release-rate
modulating polymer film comprises one or more polyester
materials.
5. The gastric residence system of claim 1, wherein the
release-rate modulating polymer film comprises at least two
different polyester materials.
6. The gastric residence system of claim 1, wherein the
release-rate modulating polymer film comprises polyester with a
repeating unit of the form: --R.sup.1--O--C(.dbd.O)-- wherein
R.sup.1 is selected from the group consisting of C.sub.1-C.sub.12
alkylene groups, ethers containing between two and twelve carbon
atoms, and polyethers containing between three and twelve carbon
atoms.
7. The gastric residence system of claim 6, wherein the R.sup.1
groups in the polymer are the same moiety, such that the polymer is
a homopolymer.
8. The gastric residence system of claim 6, wherein the R.sup.1
groups can he chosen from two or more different moieties, such that
the polymer is a heteropolymer.
9. The gastric residence system of claim 8, wherein the
heteropolymer is a block copolymer.
10. The gastric residence system of claim 8, wherein the
heteropolymer is a random copolymer.
11. The gastric residence system of claim 1, wherein the polymer
film comprises at least two different polyesters, each different
polyester with a repeating unit of the form:
--R.sup.n--O--C(.dbd.O)-- wherein: when at least two or more of the
different polyesters are homopolymers, the R.sup.n group of any one
of the homopolymers is different from the R.sup.n group of any
other of the homopolymers; and when at least two or more of the
different polyesters are heteropolymers, each heteropolymer has a
different varying pattern of R.sup.n groups than the varying
pattern of R.sup.n groups of any of the other heteropolymers; and
each R.sup.n is selected from the group consisting of
C.sub.1-C.sub.12 alkylene groups, ethers containing between two and
twelve carbon atoms, and polyethers containing between three and
twelve carbon atoms.
12. The gastric residence system of claim 1, wherein the polymer
film comprises polycaprolactone or polydioxanone.
13. The gastric residence system of claim 1, wherein the polymer
film comprises polycaprolactone of about 50,000 Mn to about 110,000
Mn.
14. The gastric residence system of claim 1, wherein the polymer
film comprises polycaprolactone of about 80,000 Mn to about 110,000
Mn.
15. The gastric residence system of claim 1, wherein the polymer
film comprises polycaprolactone of about 60,000 Mn to about 100,000
Mn.
16. The gastric residence system of claim 1, wherein the polymer
film comprises polycaprolactone having intrinsic viscosity of about
1.5 dL/g to about 2.1 dL/g.
17. The gastric residence system of claim 1, wherein the polymer
film comprises polycaprolactone having intrinsic viscosity of about
1.0 dL/g to about 2.1 dL/g.
18. The gastric residence system of any one of claims 1-17, wherein
the polymer film further comprises a porogen.
19. The gastric residence system of claim 18, wherein the porogen
comprises a water-soluble polymer, a water-soluble small molecule,
an inorganic salt, or an organic salt.
20. The gastric residence system of claim 18 or claim 19, wherein
the porogen comprises about 5% to about 40% by weight of the
film.
21. The gastric residence system of claim 18 or claim 19, wherein
the porogen comprises about 5% to about 30% by weight of the
film.
22. The gastric residence system of any one of claims 18-21,
wherein the porogen is selected from the group consisting of alkali
metal salts, sodium chloride, sodium bromide, potassium chloride,
potassium sulfate, potassium phosphate, sodium benzoate, sodium
acetate, sodium citrate, potassium nitrate, alkaline earth metal
salts, calcium chloride, calcium nitrate, transition metal salts,
ferric chloride, ferrous sulfate, zinc sulfate, cupric chloride,
saccharides, sugars, such as sucrose, glucose, fructose, mannose,
galactose, aldohexose, altrose, talose, lactose, cellulose,
monosaccharides, disaccharides, water soluble polysaccharides,
sorbitol, mannitol, organic aliphatic and aromatic oils, diols and
polyols, polyhydric alcohols, poly(alkylene glycols), polyglycols,
alkylene glycols, poly(a,m)alkylenediol esters, alkylene glycols,
poly vinylalcohol, poly vinyl pyrrolidone, water soluble polymeric
materials, Poloxamer, hypromellose (HPMC), Kolliphor RH40,
polyvinyl caprolactam, polyvinyl acetate (PVAc), polyethylene
glycol (PEG), Soluplus (copolymer of polyvinyl caprolactam,
polyvinyl acetate, and polyethylene glycol), copovidone, Eudragits
(E, RS, RL), poly(methyl vinyl ether-alt-maleic anhydride),
polyoxyethylene alkyl ethers, polysorbates, polyoxyethylene
stearates, polydextrose, polyacrylic acid, alginates, sodium starch
glycolate, crosslinked polyacrylic acid (carbopol), crosslinked PVP
(crospovidone), crosslinked cellulose (croscarmellose), calcium
silicate, xanthan gum, and gellan gum.
23. The gastric residence system of any one of claims 1-22, wherein
the polymer film further comprises a plasticizer.
24. The gastric residence system of claim 23, wherein the
plasticizer comprises triethyl citrate, triacetin, PEG, poloxamer,
tributyl citrate, or dibutyl sebacate.
25. The gastric residence system of claim 23 or claim 24, wherein
the plasticizer comprises about 1% to about 30% by weight of the
film.
26. The gastric residence system of claim 23 or claim 24, wherein
the plasticizer comprises about 5% to about 30% by weight of the
film.
27. The gastric residence system of any one of claims 1-26, wherein
the polymer film further comprises an anti-tack agent.
28. The gastric residence system of claim 27, wherein the anti-tack
agent is selected from the group consisting of magnesium stearate,
talc, and glycerol monostearate.
29. The gastric residence system of any one of claims 1-28, wherein
the polymer film further comprises a permeable component which is
permeable to the agent or salt thereof, permeable to water, or both
permeable to the agent or salt thereof and permeable to water.
30. The gastric residence system of claim 29, wherein the permeable
component is selected from the group consisting of sodium starch
glycolate (SSG), crospovidone, croscarmellose, and crosslinked
polyacrylic acid.
31. The gastric residence system of any one of claims 1-30, wherein
the carrier polymer comprises a polylactone.
32. The gastric residence system of claim 31, wherein the
polylactone of the carrier polymer comprises polycaprolactone.
33. The gastric residence system of claim 32, wherein the
polycaprolactone of the carrier polymer has an average M.sub.n of
about 50,000 to about 110,000.
34. The gastric residence system of claim 32, wherein the
polycaprolactone of the carrier polymer has an average M.sub.n of
about 60,000 to about 100,000.
35. The gastric residence system of claim 32, wherein the
polycaprolactone of the carrier polymer has an average M.sub.n of
about 80,000 to about 110,000.
36. The gastric residence system of any one of claims 1-35, wherein
the elongate members further comprise at least one excipient.
37. The gastric residence system of claim 36, wherein the at least
one excipient is selected from the group consisting of P407,
Eudragit E, PEG, Polyvinylpyrrolidone (PVP), Polyvinyl acetate
(PVAc), Polyvinyl alcohol (PVA), Eudragit RS, Eudragit RL, PLA,
PLGA, PLA-PCL, polydioxanone, crospovidone, croscarmellose, HPMCAS,
Lecithin, Taurocholate, SDS, Soluplus, fatty acids, Kolliphor RH40;
and linear block copolymers of dioxanone and ethylene glycol;
linear block copolymers of lactide and ethylene glycol; linear
block copolymers of lactide, ethylene glycol, trimethyl carbonate,
and caprolactone; linear block copolymers of lactide, glycolide,
and ethylene glycol; linear block copolymers of glycolide,
polyethylene glycol and ethylene glycol; linear copolymers of
caprolactone and glycolide; polyaxial block copolymers of
glycolide, caprolactone, and trimethylene carbonate; polyaxial
block copolymers of glycolide, trimethylene carbonate, and lactide;
polyaxial block copolymers of glycolide, trimethylene carbonate and
polypropylene succinate; polyaxial block copolymers of
caprolactone, lactide, glycolide, and trimethylene carbonate;
polyaxial block copolymers of glycolide, trimethylene carbonate,
and caprolactone; and linear block copolymers of lactide,
caprolactone, and trimethylene carbonate.
38. The gastric residence system of claim 36, wherein the at least
one excipient comprises a polyalkylene glycol.
39. The gastric residence system of any one of claims 1-38, wherein
the elongate members further comprise an anti-oxidant or further
comprise silica.
40. The gastric residence system of any one of claims 1-39, wherein
the central elastomer comprises silicone rubber.
41. The gastric residence system of any one of claims 1-40, wherein
the elongate members are affixed to the central elastomer via
linkers, wherein the linkers are configured to weaken or degrade to
allow passage of the gastric residence system through the pylorus
after the specified gastric residence period.
42. The gastric residence system of any one of claims 1-41 wherein
at least one elongate member comprises at least two segments joined
by linkers, wherein the linkers are configured to weaken or degrade
to allow passage of the gastric residence system through the
pylorus after the specified gastric residence period.
43. The gastric residence systems of claim 41 or claim 42, wherein
the linkers comprise hydroxypropyl methyl cellulose-acetate
succinate (HPMCAS) and polycaprolactone.
44. The gastric residence system of any one of claims 1-43, wherein
the system has a gastric residence period of about four days to
about ten days when administered to a human patient.
45. The gastric residence system of any one of claims 1-44, wherein
the agent or pharmaceutically acceptable salt thereof comprises
about 25% to about 60% by weight of the at least one elongate
member
46. The gastric residence system of any one of claims 1-44, wherein
the agent or pharmaceutically acceptable salt thereof comprises
about 40% to about 60% by weight of the a least one elongate
member
47. The gastric residence system of any one of claims 1-44, wherein
the agent or pharmaceutically acceptable salt thereof is present in
an amount by weight of between about 67% and about 150% of the
weight of the carrier polymer,
48. A gastric residence system providing an extended release agent
dosage form, comprising: a plurality of elongate members, wherein
at least one elongate member comprises a therapeutically effective
amount of an agent or a pharmaceutically acceptable salt thereof
and a carrier polymer, wherein the agent or pharmaceutically
acceptable salt thereof is blended with the carrier polymer such
that the agent or salt thereof is distributed throughout the at
least one elongate member, and a release-rate modulating polymer
film coating the at least one elongate member; wherein the agent or
pharmaceutically acceptable salt thereof comprises about 25% to
about 60% by weight of the at least one elongate member; wherein
the plurality of elongate members are attached to a central
elastomer; and wherein said gastric residence system provides
extended release of the agent or pharmaceutically acceptable salt
thereof.
49. A gastric residence system providing an extended release agent
dosage form, comprising: a plurality of elongate members, wherein
at least one elongate member comprises a therapeutically effective
amount of an agent or a pharmaceutically acceptable salt thereof
and a carrier polymer, wherein the agent or pharmaceutically
acceptable salt thereof is blended with the carrier polymer such
that the agent or salt thereof is distributed throughout the at
least one elongate member, and a release-rate modulating polymer
film coating the at least one elongate member; wherein the agent or
pharmaceutically acceptable salt thereof comprises about 40% to
about 60% by weight of the at least one elongate member; wherein
the plurality of elongate members are attached to a central
elastomer; and wherein said gastric residence system provides
extended release of the agent or pharmaceutically acceptable salt
thereof.
50. The gastric residence system of any one of claims 1-49, wherein
the agent or pharmaceutically acceptable salt thereof has a
difference in solubility of a factor of about 5 or more at two
different pH values between about pH 1 and about pH 6.
51. The gastric residence system of any one of claims 1-50, wherein
the gastric residence system has a pH-dependent release rate ratio
factor of about 3 or less at two different pH values between about
pH 1 and about pH 6.
52. The gastric residence system of any one of claims 1-50, wherein
the gastric residence system has a pH-dependent release rate ratio
factor of about 2 or less at two different pH values between about
pH 1 and about pH 6.
53. The gastric residence system of any one of claims 50-52,
wherein the two different pH values are pH 1.5 and pH 4.8.
54. The gastric residence system of any one of claims 50-52,
wherein the two different pH values are at least about 2 pH units
apart.
55. The gastric residence system of any one of claims 50-54,
wherein the gastric residence system has a deviation from 1 of a
pH-dependent release rate ratio factor at least about 25% less than
a deviation from 1 of a pH-dependent release rate ratio factor of a
comparison gastric residence system comprising the same components
but lacking the release-rate modulating polymer film.
56. The gastric residence system of any one of claims 50-54,
wherein the gastric residence system has a deviation from 1 of a
pH-dependent release rate ratio factor at least about 50% less than
a deviation from 1 of a pH-dependent release rate ratio factor of a
comparison gastric residence system comprising the same components
but lacking the release-rate modulating polymer film.
57. The gastric residence system of any one of claims 1-56, wherein
the system is configured to have a dissolution profile
characterized by: i) about 10% to 20% dissolution of the initial
amount of the agent or pharmaceutically acceptable salt thereof
present in the system during an initial 24 hour period in an
aqueous environment; or ii) about 20% to 40% dissolution of the
initial amount of the agent or pharmaceutically acceptable salt
thereof present in the system during an initial 48 hour period in
an aqueous environment; wherein the aqueous environment is the
stomach of a mammal, the stomach of a human patient, simulated
gastric fluid, fasted state simulated gastric fluid, or fed state
simulated gastric fluid.
58. A method of administering a gastric residence system to a
patient, comprising: administering a container containing a gastric
residence system of any one of claims 1-57 in a compacted state to
a patient, wherein the container enters the stomach of the patient
and dissolves after entry into the stomach, releasing the gastric
residence system which then adopts its uncompacted state.
59. A segment of a gastric residence system, the segment
comprising: a carrier polymer; an agent or a salt thereof; and a
release-rate modulating polymer film configured to control the
release rate of the agent or salt thereof, wherein over a seven-day
incubation of the segment in simulated gastric fluid, the amount of
the agent or salt thereof released from the segment during day 5 is
at least about 40% of the amount of agent or salt thereof released
during day 2; and wherein at least about 7% of the total amount of
agent or salt thereof in the segment is released on day 2 and at
least about 7% of the total amount of agent or salt thereof is
released on day 5.
60. A segment of a gastric residence system, the segment
comprising: a carrier polymer, an agent or a salt thereof and a
release-rate modulating polymer film configured to control the
release rate of the agent or salt thereof, wherein the release-rate
modulating polymer film is configured such that the release of
agent or salt thereof from the segment in 40% ethanol/60% simulated
gastric fluid over one hour is no more than about 40% higher
compared to release of agent or salt thereof from an equivalent
segment in 100% simulated gastric fluid over one hour.
61. A segment of a gastric residence system, the segment
comprising: a carrier polymer; an agent or a salt thereof, and a
release-rate modulating polymer film, wherein the polymer film is
configured to control the release rate of the agent or salt thereof
from the segment over a seven-day period in simulated gastric fluid
such that the release rate from the segment over any one of the
seven days varies by no more than about 25% from the average daily
total release from the segment over the seven days.
62. A segment of a gastric residence system, the segment
comprising: a carrier polymer; an agent or a salt thereof; and a
release-rate modulating polymer film, wherein the polymer film: i)
comprises about 0.1% to about 20% of the total weight of the
segment; or ii) has a thickness between about 1 micron and about 40
microns.
63. A segment of a gastric residence system, the segment
comprising: a carrier polymer; an agent or a salt thereof and a
release-rate modulating polymer film, wherein the polymer film: i)
comprises about 0.1% to about 10% of the total weight of the
segment; or ii) has a thickness between about 1 micron and about 20
microns.
64. The segment of any one of claims 59-63, wherein the polymer
film comprises polyester with a repeating unit of the form:
--R.sup.1--O--C(.dbd.O)-- wherein R.sup.1 is selected from the
group consisting of C.sub.1-C.sub.12 alkylene groups, ethers
containing between two and twelve carbon atoms, and polyethers
containing between three and twelve carbon atoms.
65. A gastric residence system for administration to a patient,
comprising: an elastomer component, and at least three elongate
members attached to the elastomer component, wherein each elongate
member comprises a proximal end, a distal end, and an outer surface
therebetween, the proximal end of each elongate member is attached
to the elastomer component and projects radially from the elastomer
component, each elongate member has its distal end not attached to
the elastomer component and located at a larger radial distance
from the elastomer component than the proximal end; wherein at
least one elongate member comprises a segment of any one of claims
59-63.
66. A gastric residence system for administration to a patient,
comprising at least one segment of any one of claims 59-63.
67. A method of making a segment of a gastric residence system
comprising: coating a segment comprising a carrier polymer and an
agent or a salt thereof with a solution of a polymer film
formulation to produce a film-coated segment; and drying the
film-coated segment.
68. The method of claim 67, wherein the coating comprises dip
coating, pan coating, spray coating, or fluidized bed coating.
69. A method of making a segment of a gastric residence system
coated with a release-rate modulating polymer film or an elongate
member of a gastric residence system coated with a release-rate
modulating polymer film, comprising: co-extruding a polymer film
and a mixture of a carrier polymer and an agent or a
pharmaceutically acceptable salt thereof to form the segment or
elongate member.
70. The gastric residence system of any one of claim 1-57 or 65-66,
or the segment of a gastric residence system of any one of claims
59-64, wherein the agent or pharmaceutically salt thereof is
selected from the group consisting of donepezil, doxycycline,
risperidone, a pharmaceutically acceptable salt of donepezil, a
pharmaceutically acceptable salt of doxycycline, or a
pharmaceutically acceptable salt of risperidone.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority benefit of U.S. Provisional
Patent Application No. 62/517,732 filed Jun. 9, 2017, of U.S.
Provisional Patent Application No. 62/566,111 filed Sep. 29, 2017,
and of U.S. Provisional Patent Application No. 62/652,128 filed
Apr. 3, 2018. The entire contents of those patent applications are
hereby incorporated by reference herein.
FIELD OF THE INVENTION
[0002] The invention relates to systems which remain in the stomach
for extended periods for sustained release of pharmaceuticals, and
methods of use thereof.
BACKGROUND OF THE INVENTION
[0003] Gastric residence systems are delivery systems for agents
which remain in the stomach for days to weeks, or even over longer
periods, during which time drugs or other agents can elute from the
systems for absorption in the gastrointestinal tract. Examples of
such systems are described in International Patent Application Nos.
WO 2015/191920, WO 2015/191925, WO 2017/070612, WO 2017/100367, and
PCT/U52017/034856.
[0004] Gastric residence systems are designed to be administered to
the stomach of a patient, typically in a capsule which is swallowed
or introduced into the stomach by an alternate method of
administration (for example, feeding tube or gastric tube). Upon
dissolution of the capsule in the stomach, the systems expand or
unfold to a size which remains in the stomach and resists passage
through the pyloric sphincter over the desired residence period
(such as three days, seven days, two weeks, etc.). This requires
mechanical stability over the desired residence period. Over the
period of residence, the system releases an agent or agents, such
as one or more drugs, preferably with minimal burst release, which
requires careful selection of the carrier material for the agent in
order to provide the desired release profile. While resident in the
stomach, the system should not interfere with the normal passage of
food or other gastric contents. The system should pass out of the
stomach at the end of the desired residence time, and be readily
eliminated from the patient. If the system prematurely passes from
the stomach into the small intestine, it should not cause
intestinal obstruction, and again should be readily eliminated from
the patient. These characteristics require careful selection of the
materials from which the system is constructed, and the dimensions
and arrangement of the system.
[0005] The current invention describes the use of release
rate-modulating films for use in gastric residence systems, which
provide good control over release rates of agents from the
systems.
SUMMARY OF THE INVENTION
[0006] The invention provides gastric residence systems which have
segments covered with release rate-modulating polymer films. The
invention also provides elongate members of gastric residence
systems which have segments covered with release rate-modulating
polymer films. The invention also provides segments covered with
release rate-modulating polymer films suitable for use in gastric
residence systems. The invention also provides elongate members
covered with release rate-modulating polymer films suitable for use
in gastric residence systems. Methods of making the segments,
elongate members, and gastric residence systems are also provided.
Methods of using the gastric residence systems are also
provided.
[0007] In some embodiments, the invention provides gastric
residence systems which comprise a therapeutically effective amount
of an agent or a pharmaceutically acceptable salt thereof, where
the gastric residence system has a compacted configuration and an
uncompacted configuration, the gastric residence system comprises a
plurality of elongate members affixed to a central elastomer, each
elongate member comprises at least two segments joined by linkers,
where the linkers are configured such that they no longer join the
at least two segments of each elongate member after a specified
gastric residence period; and where the elongate members comprise a
carrier polymer, and the agent or the pharmaceutically acceptable
salt thereof; where the gastric residence system is configured to
release the agent or the pharmaceutically acceptable salt thereof
over the specified gastric residence period. At least one of the
linkers can comprise an enteric polymer, or can comprise a polymer
that degrades in a time-dependent manner in an aqueous environment.
The gastric residence period of the system can be about four days,
at least about four days, about seven days, or at least about seven
days. In some embodiments, the gastric residence systems as
disclosed herein can have a gastric residence period of about four
days to about eight days when administered to a human patient. In
some embodiments, the gastric residence systems as disclosed herein
can have a gastric residence period of about four days to about ten
days when administered to a human patient. In some embodiments, the
gastric residence systems as disclosed herein can have a gastric
residence period of about seven days, or at least about seven days,
when administered to a human patient. In some embodiments, the
gastric residence systems as disclosed herein can have a gastric
residence period of about seven days to about ten days when
administered to a human patient
[0008] In any of the embodiments described herein, the invention
can provide gastric residence systems which comprise a
therapeutically effective amount of an agent or a pharmaceutically
acceptable salt thereof, where the gastric residence system has a
compacted configuration and an uncompacted configuration, the
gastric residence system comprises a plurality of elongate members
affixed to a central elastomer, each elongate member comprises at
least two segments joined by linkers, where the linkers are
configured to weaken or degrade to allow passage of the gastric
residence system through the pylorus after the specified gastric
residence period (for example, the linkers may soften and become
flexible, or the linkers may no longer join the at least two
segments of each elongate member after the specified gastric
residence period); and where the segments of the elongate members
comprise a carrier polymer and the adamantane-class drug or the
pharmaceutically acceptable salt thereof, or the segments of the
elongate members comprise a) a carrier polymer, b) at least one
excipient, and c) the agent or the pharmaceutically acceptable salt
thereof; where the gastric residence system is configured to
release the agent or the pharmaceutically acceptable salt thereof
over the specified gastric residence period. At least one of the
linkers can comprise an enteric polymer, or can comprise a polymer
that degrades in a time-dependent manner in an aqueous environment.
The gastric residence period of the system can be about four days,
at least about four days, about seven days, or at least about seven
days. The gastric residence period of the system can be about four
days to about ten days, about four days to about eight days, or
about seven days to about ten days.
[0009] In any of the embodiments described herein, the invention
can provide gastric residence systems which comprise a
therapeutically effective amount of an adamantane-class drug or a
pharmaceutically acceptable salt thereof, where the gastric
residence system has a compacted configuration and an uncompacted
configuration, the gastric residence system comprises a plurality
of elongate members affixed to a central elastomer by linkers,
where the linkers are configured to weaken or degrade to allow
passage of the gastric residence system through the pylorus after
the specified gastric residence period (for example, the linkers
may soften and become flexible, or the linkers may no longer join
the elongate members to the central elastomer after the specified
gastric residence period). The elongate members comprise a carrier
polymer and the adamantane-class drug or the pharmaceutically
acceptable salt thereof. In another embodiment, the elongate
members further comprise at least one excipient. The gastric
residence system is configured to release the adamantane-class drug
or the pharmaceutically acceptable salt thereof over the specified
gastric residence period. The adamantine-class drug or a
pharmaceutically acceptable salt thereof can be memantine or a
pharmaceutically acceptable salt thereof. At least one of the
linkers can comprise an enteric polymer, or can comprise a polymer
that degrades in a time-dependent manner in an aqueous environment.
The gastric residence period of the system can be about four days,
at least about four days, about seven days, or at least about seven
days. The gastric residence period of the system can be about four
days to about ten days, about four days to about eight days, or
about seven days to about ten days.
[0010] In any of the embodiments described herein, the invention
can provide gastric residence systems which comprise a
therapeutically effective amount of risperidone or a
pharmaceutically acceptable salt thereof, where the gastric
residence system has a compacted configuration and an uncompacted
configuration, the gastric residence system comprises a plurality
of elongate members affixed to a central elastomer by linkers,
where the linkers are configured to weaken or degrade to allow
passage of the gastric residence system through the pylorus after
the specified gastric residence period (for example, the linkers
may soften and become flexible, or the linkers may no longer join
the elongate members to the central elastomer after the specified
gastric residence period). The elongate members comprise a carrier
polymer and risperidone or pharmaceutically acceptable salt
thereof. In another embodiment, the elongate members further
comprise at least one excipient. The gastric residence system is
configured to release risperidone or the pharmaceutically
acceptable salt thereof over the specified gastric residence
period. At least one of the linkers can comprise an enteric
polymer, or can comprise a polymer that degrades in a
time-dependent manner in an aqueous environment. The gastric
residence period of the system can be about four days, at least
about four days, about seven days, or at least about seven days.
The gastric residence period of the system can be about four days
to about ten days, about four days to about eight days, or about
seven days to about ten days.
[0011] In any of the embodiments described herein, the invention
can provide gastric residence systems which comprise a
therapeutically effective amount of doxycycline or a
pharmaceutically acceptable salt thereof, where the gastric
residence system has a compacted configuration and an uncompacted
configuration, the gastric residence system comprises a plurality
of elongate members affixed to a central elastomer by linkers,
where the linkers are configured to weaken or degrade to allow
passage of the gastric residence system through the pylorus after
the specified gastric residence period (for example, the linkers
may soften and become flexible, or the linkers may no longer join
the elongate members to the central elastomer after the specified
gastric residence period). The elongate members comprise a carrier
polymer and doxycycline or pharmaceutically acceptable salt
thereof. In another embodiment, the elongate members further
comprise at least one excipient. The gastric residence system is
configured to release doxycycline or the pharmaceutically
acceptable salt thereof over the specified gastric residence
period. At least one of the linkers can comprise an enteric
polymer, or can comprise a polymer that degrades in a
time-dependent manner in an aqueous environment. The gastric
residence period of the system can be about four days, at least
about four days, about seven days, or at least about seven days.
The gastric residence period of the system can be about four days
to about ten days, about four days to about eight days, or about
seven days to about ten days.
[0012] In any of the embodiments described herein, the invention
can provide gastric residence systems which comprise a
therapeutically effective amount of donepezil or a pharmaceutically
acceptable salt thereof, where the gastric residence system has a
compacted configuration and an uncompacted configuration, the
gastric residence system comprises a plurality of elongate members
affixed to a central elastomer by linkers, where the linkers are
configured to weaken or degrade to allow passage of the gastric
residence system through the pylorus after the specified gastric
residence period (for example, the linkers may soften and become
flexible, or the linkers may no longer join the elongate members to
the central elastomer after the specified gastric residence
period). The elongate members comprise a carrier polymer and
donepezil or pharmaceutically acceptable salt thereof. In another
embodiment, the elongate members further comprise at least one
excipient. The gastric residence system is configured to release
donepezil or the pharmaceutically acceptable salt thereof over the
specified gastric residence period. At least one of the linkers can
comprise an enteric polymer, or can comprise a polymer that
degrades in a time-dependent manner in an aqueous environment. The
gastric residence period of the system can be about four days, at
least about four days, about seven days, or at least about seven
days. The gastric residence period of the system can be about four
days to about ten days, about four days to about eight days, or
about seven days to about ten days.
[0013] In some embodiments, the invention provides gastric
residence systems which comprise an agent or a pharmaceutically
acceptable salt thereof, where the gastric residence system has a
compacted configuration and an uncompacted configuration, the
gastric residence system comprises a plurality of elongate members
affixed to a central elastomer by linkers, where the linkers are
configured such that they no longer join the elongate members to
the central elastomer after a specified gastric residence period.
The elongate members comprise a carrier polymer and the agent or
the pharmaceutically acceptable salt thereof. In another
embodiment, the elongate members further comprise at least one
excipient. The gastric residence system is configured to release
the agent or the pharmaceutically acceptable salt thereof over the
specified gastric residence period. At least one of the linkers can
comprise an enteric polymer, or can comprise a polymer that
degrades in a time-dependent manner in an aqueous environment. The
gastric residence period of the system can he about four days, at
least about four days, about seven days, or at least about seven
days. The gastric residence period of the system can be about four
days to about ten days, about four days to about eight days, or
about seven days to about ten days.
[0014] In any of the gastric residence systems disclosed herein,
the carrier polymer can be polycaprolactone. One or more additional
excipients can be mixed in with the carrier polymer. The one or
more additional excipients can be selected from the group
consisting of soluble excipients, insoluble wicking excipients,
degradable excipients, insoluble swellable excipients, and
surfactants. The one or more additional excipients can be selected
from the group consisting of P407, Eudragit E, PEG,
Polyvinylpyrrolidone (PVP), Polyvinyl acetate (PVAc), Polyvinyl
alcohol (PVA), Eudragit RS, Eudragit RL, PLA, PLGA, PLA-PCL,
polydioxanone, Crospovidone, Croscarmellose, HPMCAS, Lecithin,
Taurocholate, SDS, Soluplus, Fatty acids, Kolliphor RH40; and
linear block copolymers of dioxanone and ethylene glycol; linear
block copolymers of lactide and ethylene glycol; linear block
copolymers of lactide, ethylene glycol, trimethyl carbonate, and
caprolactone; linear block copolymers of lactide, glycolide, and
ethylene glycol; linear block copolymers of glycolide, polyethylene
glycol, and ethylene glycol; linear copolymers of caprolactone and
glycolide; polyaxial block copolymers of glycolide, caprolactone,
and trimethylene carbonate; polyaxial block copolymers of
glycolide, trimethylene carbonate, and lactide; polyaxial block
copolymers of glycolide, trimethylene carbonate and polypropylene
succinate; polyaxial block copolymers of caprolactone, lactide,
glycolide, and trimethylene carbonate; polyaxial block copolymers
of glycolide, trimethylene carbonate, and caprolactone; and linear
block copolymers of lactide, caprolactone, and trimethylene
carbonate, such as linear block copolymers of dioxanone (80%) and
ethylene glycol (20%); linear block copolymers of lactide (60%) and
ethylene glycol (40%); linear block copolymers of lactide (68%),
ethylene glycol (20%), trimethyl carbonate (10%), and caprolactone
(2%); linear block copolymers of lactide (88%), glycolide (8%), and
ethylene glycol (4%); linear block copolymers of glycolide (67%),
polyethylene glycol (28%), and ethylene glycol (5%); linear
copolymers of caprolactone (95%) and glycolide (5%); polyaxial
block copolymers of glycolide (68%), caprolactone (29%), and
trimethylene carbonate (3%); polyaxial block copolymers of
glycolide (86%), trimethylene carbonate (9%), and lactide (5%);
polyaxial block copolymers of glycolide (70%), trimethylene
carbonate (27%) and polypropylene succinate (2%); polyaxial block
copolymers of caprolactone (35%), lactide (34%), glycolide (17%),
and trimethylene carbonate (14%); polyaxial block copolymers of
glycolide (55%), trimethylene carbonate (25%), and caprolactone
(20%); and linear block copolymers of lactide (39%), caprolactone
(33%), and trimethylene carbonate (28%).
[0015] In any of the gastric residence systems disclosed herein,
when at least one of the linkers is an enteric polymer, the enteric
polymer can be selected from the group consisting of
poly(methacrylic acid-co-ethyl acrylate), cellulose acetate
phthalate, cellulose acetate succinate, hydroxypropyl
methylcellulose phthalate, methylcellulose phthalate,
ethylhydroxycellulose phthalate, polyvinylacetatephthalate,
polyvinylbutyrate acetate, vinyl acetate-maleic anhydride
copolymer, styrene-maleic mono-ester copolymer, methacrylic acid
methylmethacrylate copolymer, methyl acrylate-methacrylic acid
copolymer, methacrylate-methacrylic acid-octyl acrylate copolymer;
and copolymers, mixtures, blends and combinations thereof.
Hydroxypropyl methylcellulose acetate succinate (HPMCAS) is a
particularly useful enteric polymer, and can be used alone or in a
copolymer, mixture, blend, or combination with any one or more of
the other foregoing enteric polymers.
[0016] In any of the gastric residence systems disclosed herein
having a central elastomer, the central elastomer can comprise
silicone rubber.
[0017] In any of the gastric residence systems disclosed herein,
the system can further comprise a dispersant selected from the
group comprising silicon dioxide, hydrophilic fumed silicon
dioxide, a stearate salt, calcium stearate, magnesium stearate,
microcrystalline cellulose, carboxymethylcellulose, hydrophobic
colloidal silica, hypromellose, magnesium aluminum silicate, a
phospholipid, a polyoxyethylene stearate, zinc acetate, alginic
acid, lecithin, a fatty acid, sodium lauryl sulfate, a non-toxic
metal oxide, aluminum oxide, a porous inorganic material, and a
polar inorganic material.
[0018] In any of the gastric residence systems disclosed herein,
the agent or pharmaceutically acceptable salt thereof can comprise
particles of the agent or a pharmaceutically acceptable salt
thereof in the form of particles disposed in the carrier polymer,
where at least about 80% of the mass of particles have sizes
between about 1 micron and about 50 microns in diameter.
[0019] In any of the gastric residence systems disclosed herein,
the gastric residence system can comprise about 10 mg to about 600
mg of agent or a pharmaceutically acceptable salt thereof.
[0020] In one embodiment, the invention provides a formulation for
extended release of an agent or a pharmaceutically acceptable salt
thereof, comprising about 10% to about 30% of an agent or a
pharmaceutically acceptable salt thereof; about 0.1% to about 4% of
silica; about 5% to about 30% of an acrylate polymer or co-polymer;
and about 0.2% to about 10% of a polyalkylene glycol; where the
remainder of the composition comprises a polylactone. The
formulation can further comprise about 0.1% to about 2% of an
anti-oxidant material. The anti-oxidant material can comprise one
or more compounds selected from the group consisting of Vitamin E,
a tocopherol, a Vitamin E ester, a tocopherol ester, ascorbic acid,
or a carotene, such as alpha-tocopherol, Vitamin E succinate,
alpha-tocopherol succinate, Vitamin E acetate, alpha-tocopherol
acetate, Vitamin E nicotinate, alpha-tocopherol nicotinate, Vitamin
E linoleate, or alpha-tocopherol linoleate. (Vitamin E can refer to
alpha-tocopherol, beta-tocopherol, gamma-tocopherol,
delta-tocopherol, alpha-tocotrienol, beta-tocotrienol,
gamma-tocotrienol, or delta-tocotrienol, or to any combinations of
any two or more of the foregoing.) The silica can comprise
hydrophilic fumed silica particles. The acrylate polymer or
co-polymer can comprise a co-polymer of ethyl acrylate, methyl
methacrylate and trimethylammonioethyl methacrylate, such as a
co-polymer comprising ethyl acrylate, methyl methacrylate and
trimethylammonioethyl methacrylate in a molar ratio of about
1:2:0.1. The polyalkylene glycol can be selected from the group
consisting of polyethylene glycol (PEG), polypropylene glycol
(PPG), and a block copolymer of PEG and PPG. When the polyalkylene
glycol comprises a block copolymer of PEG and PPG, it can comprise
a copolymer of the formula
H--(OCH2CH2).sub.x-(O--CH(CH3)CH2).sub.y-(OCH2CH2).sub.z-OH, where
x and z are about 101 and y is about 56. The polylactone can
comprise polycaprolactone, such as a polycaprolactone having an
average Mn of about 60,000 to about 100,000, an average Mn of about
75,000 to about 85,000, or an average Mn of about 80,000 (80 k
PCL).
[0021] In some embodiments, the invention provides one or more
elongate members formed from a material comprising a formulation
for extended release of an agent or a pharmaceutically acceptable
salt thereof as described herein. In some embodiments, the
invention provides gastric residence systems comprising one or more
elongate members formed from a material comprising a formulation
for extended release of an agent or a pharmaceutically acceptable
salt thereof as described herein.
[0022] In one embodiment, the invention provides a method of making
a gastric residence system, comprising preparing at least three
elongate members formed from a material comprising any of the
formulations for extended release of an agent or a pharmaceutically
acceptable salt thereof as described herein; and attaching the
elongate members to a central elastomer, to form a gastric
residence system having elongate members projecting radially from
the central elastomer.
[0023] In any embodiment of the methods of treatment disclosed
herein, the gastric residence system can administered to the
patient on an approximately weekly basis over a period of at least
about one month, at least about two months, at least about three
months, or indefinitely, or for a period up to about one month,
about two months or about three months.
[0024] The invention additionally provides gastric residence
systems for administration of agents or salts thereof which have
segments or elongate members covered with release rate-modulating
polymer films, as well as elongate members of such gastric
residence systems which have segments covered with release
rate-modulating polymer film, segments covered with release
rate-modulating polymer films suitable for use in such gastric
residence systems, and elongate members covered with release
rate-modulating polymer films suitable for use in such gastric
residence systems. Methods of making the segments, elongate
members, and gastric residence systems containing agents and salts
thereof are also provided. Methods of using the gastric residence
systems containing agents and salts thereof are also provided.
[0025] In one embodiment, the invention provides a segment of a
gastric residence system, the segment comprising a carrier polymer;
an agent or a salt thereof; and a release-rate modulating polymer
film configured to control the release rate of the agent, wherein
over a seven-day incubation of the segment in simulated gastric
fluid, the amount of the agent or salt thereof released during day
5 is at least about 40% of the amount of agent or salt thereof
released during day 2; and wherein at least about 7% of the total
amount of agent in the segment is released on day 2 and at least
about 7% of the total amount of agent is released on day 5.
[0026] In one embodiment, the invention provides a segment of a
gastric residence system, the segment comprising a carrier polymer;
an agent or a salt thereof; and a release-rate modulating polymer
film configured to control the release rate of the agent, wherein
over a seven-day incubation of the segment in simulated gastric
fluid, the amount of the agent or salt thereof released from the
segment during day 7 is at least about 20; of the amount of agent
or salt thereof released during day 1; and wherein at least about
4% of the total amount of agent in the segment is released on day 1
and at least about 4% of the total amount of agent is released on
day 7.
[0027] In one embodiment, the invention provides a segment of a
gastric residence system, the segment comprising a carrier polymer,
an agent or a salt thereof; and a release-rate modulating polymer
film configured to control the release rate of the agent, wherein
the release-rate modulating polymer film is configured such that
the release of agent from the segment in 40% ethanol/60% simulated
gastric fluid over one hour is no more than about 40% higher
compared to release of agent from an equivalent segment in 100%
simulated gastric fluid over one hour,
[0028] In one embodiment, the invention provides a segment of a
gastric residence system, the segment comprising a carrier polymer,
an agent or a salt thereof; and a release-rate modulating polymer
film configured to control the release rate of the agent, wherein
the release-rate modulating polymer film is configured such that
the release of agent from the segment in 40% ethanol/60% simulated
gastric fluid over one hour is at least about 40% lower than the
release of agent from a second segment in 40% ethanol/60% simulated
gastric fluid over one hour, the second segment comprising the same
combination of carrier polymer and agent or salt thereof but
lacking the release-rate modulating polymer film.
[0029] In one embodiment, the invention provides a segment of a
gastric residence system, the segment comprising a carrier polymer,
an agent or a salt thereof; and a release-rate modulating polymer
film configured to control the release rate of the agent, wherein
the release-rate modulating polymer film is configured such that
the release of agent from the segment in simulated gastric fluid
over an initial 6 hour period is at least about 40% lower than the
release of agent from a second segment in simulated gastric fluid
over an initial 6 hour period, the second segment comprising the
same combination of carrier polymer and agent or salt thereof but
lacking the release-rate modulating polymer film; and wherein the
release of agent from the segment in simulated gastric fluid over a
seven-day period is at least about 60%, at least 70%, or at least
80% of the total amount of agent originally present in the
segment.
[0030] In one embodiment, the invention provides a segment of a
gastric residence system, the segment comprising a carrier polymer;
an agent or a salt thereof; and a release-rate modulating polymer
film, wherein the polymer film is configured to control the release
rate of the agent such that a best-fit linear regression model of
the release rate of agent from the segment in simulated gastric
fluid has a coefficient of determination R.sup.2 of at least about
0.8, at least 0.85, or at least 0.9 over an initial period of seven
days; and wherein the segment releases about 40% to about 60% of
the agent or salt thereof within a time of about 40% to about 60%
of the seven-day period.
[0031] In one embodiment, the invention provides a segment of a
gastric residence system, the segment comprising a carrier polymer;
an agent or a salt thereof; and a release-rate modulating polymer
film, wherein the polymer film is configured to control the release
rate of the agent from the segment over a seven-day period in
simulated gastric fluid such that the release rate from the segment
over any one of the seven days varies by no more than about 25%
from the average daily total release from the segment over the
seven days.
[0032] In any of the embodiments of the invention described herein,
the release-rate modulating polymer film can comprise one or more
polyester materials. The polymer film can comprise polyester with a
repeating unit of the form: --R.sup.1--O--C(.dbd.O)--, wherein
R.sup.1 is selected from the group consisting of C.sub.1-C.sub.12
alkylene groups, ethers containing between two and twelve carbon
atoms, and polyethers containing between three and twelve carbon
atoms. The polymer film can comprise polycaprolactone or
polydioxanone, such as polycaprolactone of about 10,000 to about
150,000 Mn, polycaprolactone of about 50,000 Mn to about 110,000
Mn, polycaprolactone of about 80,000 Mn to about 110,000 Mn,
polycaprolactone of about 60,000 Mn to about 100,000 Mn,
polycaprolactone of about 90,000 Mn, polycaprolactone of about
80,000 Mn, polycaprolactone of about 70,000 Mn, or polycaprolactone
having intrinsic viscosity of about 1.0 dL/g to about 2.5 dL/g,
about 1.0 dL/g to about 2.1 dL/g, or about 1.5 dL/g to about 2.1
dL/g.
[0033] In any of the embodiments of the invention described herein,
the release-rate modulating polymer film can comprise one or more
porogens. The porogen can comprise a water-soluble polymer, a
water-soluble small molecule, an inorganic salt, or an organic
salt. The porogen can comprise about 1% to about 40% by weight of
the film. The porogen can comprise about 1% to about 30% by weight
of the film. The porogen can comprise about 5% to about 40% by
weight of the film. The porogen can comprise about 5% to about 30%
by weight of the film. The porogen can be selected from the group
consisting of alkali metal salts, sodium chloride, sodium bromide,
potassium chloride, potassium sulfate, potassium phosphate, sodium
benzoate, sodium acetate, sodium citrate, potassium nitrate,
alkaline earth metal salts, calcium chloride, calcium nitrate,
transition metal salts, ferric chloride, ferrous sulfate, zinc
sulfate, cupric chloride, saccharides, sugars, such as sucrose,
glucose, fructose, mannose, galactose, aldohexose, altrose, talose,
lactose, cellulose, monosaccharides, disaccharides, water soluble
polysaccharides, sorbitol, mannitol, organic aliphatic and aromatic
oils, dials and polyols, polyhydric alcohols, poly(alkylene
glycols), polyglycols, alkylene glycols, poly(a,m)alkylenediol
esters, alkylene glycols, poly vinylalcohol, poly vinyl
pyrrolidone, water soluble polymeric materials. Poloxamer,
hypromellose Kolliphor RH40, polyvinyl caprolactam, polyvinyl
acetate (PVAc), polyethylene glycol (PEG) Soluplus (copolymer of
polyvinyl caprolactam, polyvinyl acetate, and polyethylene glycol),
copovidone, Eudragits (E, RS, RL), poly(methyl vinyl
ether-alt-maleic anhydride), polyoxyethylene alkyl ethers,
polysorbates, polyoxyethylene stearates, polydextrose, polyacrylic
acid, alginates, sodium starch glycolate, crosslinked polyacrylic
acid (carbopol), crosslinked PVP (crospovidone), crosslinked
cellulose (croscarmellose), calcium silicate, xanthan gum, and
gellan gum. The porogen can be selected from the group consisting
of povidone, copovidone, and polyoxyl castor oil.
[0034] In one embodiment, the invention provides a segment of a
gastric residence system, the segment comprising a carrier polymer;
an agent or a salt thereof; and a release-rate modulating polymer
film, wherein the polymer film comprises a material selected from
the group consisting of polycaprolactone, cellulose acetate, and
ethyl cellulose.
[0035] In any of the embodiments disclosed herein, the release-rate
modulating polymer film can comprise about 0.1% to about 20% of the
total weight of the segment. In any of the embodiments disclosed
herein, the release-rate modulating polymer film can comprise about
0.1% to about 15% of the total weight of the segment. In any of the
embodiments disclosed herein, the release-rate modulating polymer
film can comprise about 0.1% to about 10% of the total weight of
the segment, about 0.1% to about 5% of the total weight of the
segment, about 0.5% to about 5% of the total weight of the segment,
about 0.5% to about 2% of the total weight of the segment, or about
1% to about 2% of the total weight of the segment.
[0036] In any of the embodiments disclosed herein, the release-rate
modulating polymer film can comprise a thickness between about 1
micron and about 20 microns, such as between about 5 microns and
about 15 microns.
[0037] In any of the embodiments disclosed herein, the release-rate
modulating polymer film can further comprise a plasticizer. The
plasticizer can comprise about 1% to about 40% by weight of the
film, such as about 1% to about 30%, or about 1% to about 20%, or
about 1% to about 15%, or about 5% to about 20%, or about 10% to
about 20%. The plasticizer can be selected from the group
consisting of phthalates, phosphates, citrates, tartrates,
adipates, sebacates, sulfonamides, succinates, glycolates,
glycerolates, benzoates, myristates, halogenated phenyls,
triacetin, triethyl citrate, PEG, and poloxamer. The plasticizer
can be selected from the group consisting of triethyl citrate and
triacetin.
[0038] In any of the embodiments disclosed herein, the release-rate
modulating polymer film can further comprise a permeable component
which is permeable to the agent or salt thereof and permeable to
water. The permeable component can be a polymer or a swellable
material. The permeable component can comprise about 1% to about
30% by weight of the film. The permeable component can be selected
from the group consisting of SSG, crospovidone, croscarmellose, and
Carbopol (PAA; polyacrylic acid). At least one of the rate of
passage of water and the rate of passage of agent or salt thereof
through the permeable component should be higher, as compared to
the rate of passage of water or the rate of passage of agent
through the release-rate modulating polymer film lacking permeable
agent and lacking pores produced by removal of porogens. In various
embodiments, the rate of passage of water and the rate of passage
of agent or salt thereof through the permeable component is up to
about 1.5 times, up to about 2 times, up to about 3 times, up to
about 4 times, up to about 5 times, up to about 6 times, up to
about 7 times, up to about 8 times, about to about 10 times, up to
about 15 times, up to about 20 times, up to about 25 times, up to
about 50 times, or up to about 100 times faster, as compared to the
rate of passage of water or the rate of passage of agent through
the release-rate modulating polymer film lacking permeable agent
and lacking pores produced by removal of porogens.
[0039] The invention further provides gastric residence systems for
administration to a patient, comprising at least one segment of any
of the segment embodiments disclosed herein.
[0040] The invention further provides gastric residence systems for
administration to a patient, comprising an elastomer component, and
at least three elongate members attached to the elastomer
component, wherein each elongate member comprises a proximal end, a
distal end, and an outer surface therebetween, the proximal end of
each elongate member is attached to the elastomer component and
projects radially from the elastomer component, each elongate
member has its distal end not attached to the elastomer component
and located at a larger radial distance from the elastomer
component than the proximal end; wherein at least one elongate
member comprises a segment of any of the segment embodiments
disclosed herein, such as a segment coated with a release
rate-modulating polymer film or wherein at least one elongate
member is coated with a release rate-modulating polymer film. The
central elastomer of the gastric residence system can be formed
from liquid silicone rubber. The elongate members of the gastric
residence system can be attached to the central elastomer via a
disintegrating matrix, such as a disintegrating matrix comprising
HPMC-AS and polycaprolactone.
[0041] The invention further provides methods of making a segment
of a gastric residence system comprising coating a segment
comprising a carrier polymer and an agent or a salt thereof with a
solution of a polymer film formulation to produce a film-coated
segment; and drying the film-coated segment. The coating can be
performed by dip coating, pan coating, spray coating, or fluidized
bed coating. The solvent used in the solution of polymer film
formulation can comprise an organic solvent, such as ethyl acetate,
dichloromethane, acetone, isopropyl alcohol, or any combination
thereof,
[0042] The invention further provides methods of making an elongate
member of a gastric residence system comprising coating an elongate
member comprising a carrier polymer and an agent or a
pharmaceutically acceptable salt thereof with a solution of a
polymer film formulation to produce a film-coated elongate member;
and drying the film-coated elongate member. The coating can be
performed by dip coating, pan coating, spray coating, or fluidized
bed coating. The solvent used in the solution of polymer film
formulation can comprise an organic solvent, such as ethyl acetate,
dichloromethane, acetone, isopropyl alcohol, or any combination
thereof. The invention further provides a method of making an
elongate member of a gastric residence system comprising
co-extruding a polymer film and a mixture of a carrier polymer and
an agent or a pharmaceutically acceptable salt thereof.
[0043] The invention further provides a method of making a segment
of a gastric residence system comprising co-extruding a polymer
film and a mixture of a carrier polymer and an agent or a salt
thereof.
[0044] The invention further comprises methods of administering a
gastric residence system to a patient, comprising administering a
container containing any embodiment of the gastric residence
systems disclosed herein in a compacted state to a patient, wherein
the container enters the stomach of the patient and dissolves after
entry into the stomach, releasing the gastric residence system
which then adopts its uncompacted state. Preferably, the patient is
a human. The container containing the gastric residence system can
be administered by swallowing, by feeding tube, or by gastrostomy
tube.
[0045] In any of the embodiments of the gastric residence systems,
elongate members of gastric residence systems, segments, or
segments covered with a release rate-modulating polymer film, the
agent in the systems, members, or segments does not comprise an
adamantane-class drug or a pharmaceutically acceptable salt
thereof. In any of the embodiments of the gastric residence
systems, elongate members of gastric residence systems, segments,
or segments covered with a release rate-modulating polymer film,
the agent in the systems, members, or segments does not comprise
memantine; amantadine; adapromine; nitromemantine; rimantadine;
bromantane; tromantadine; neramexane; or a pharmaceutically
acceptable salt of memantine, amantadine, adapromine,
nitromemantine, rimantadine, bromantane, tromantadine, or
neramexane.
[0046] In any of the embodiments of the release rate-modulating
polymer films, or any of the embodiments of segments covered with a
release rate-modulating polymer film, the release rate-modulating
polymer film do not contain agents; that is, the films do not
contain any substance intended for therapeutic, diagnostic, or
nutritional use.
[0047] In any of the embodiments of the release rate-modulating
polymer films, or any of the embodiments of segments covered with a
release rate-modulating polymer film, the release-rate modulating
polymer film does not add substantially to the strength of the
carrier polymer-agent segment that it covers.
[0048] It is contemplated that any features from any embodiment
disclosed herein can be combined with any features from any other
embodiment disclosed herein where possible. In this fashion, hybrid
configurations of the disclosed features are within the scope of
the present invention.
[0049] In any of the embodiments disclosed herein, the term "about"
used with numerical values can indicate that both the value
specified, as well as values reasonably close to the value
specified, are included.
BRIEF DESCRIPTION OF THE DRAWINGS
[0050] FIG. 1A shows a stellate design of a gastric residence
system in its uncompacted state.
[0051] FIG. 1B shows a stellate design of a gastric residence
system in a compacted or folded state.
[0052] FIG. 1C shows a ring design of a gastric residence system in
an uncompacted state.
[0053] FIG. 2A depicts tapering release profiles for representative
formulations of memantine hydrochloride over time.
[0054] FIG. 2B depicts the linear relationship between the square
of cumulative release and time for representative monolithic matrix
based formulations, which is consistent with the Higuchi model for
matrix-based drug release.
[0055] FIG. 2C depicts linearity versus extent of release for about
50 formulations of memantine hydrochloride studied.
[0056] FIG. 3A depicts compositions of coating solutions used in
ethanol release studies.
[0057] FIGS. 3B, 3C, 3D, and 3E depict drug release profiles for
coating C5 (1 g Eudragit RS in 3 mL dichloromethane) on M18 release
(FIG. 3B), coating C8 (1 g 55K PCL in 6 mL dichloromethane) on M18
release (FIG. 3C), coating C25 (1 g ethyl cellulose in 15 mL
acetone) on M18 release (FIG. 3D), and coating C31 (1.5 g cellulose
acetate in 15 mL acetone) on M18 release (FIG. 3E) in FaSSGF for 7
days and in 40% ethanol, 60% FaSSGF for one hour followed by the
remainder of the 7 days in FaSSGF.
[0058] FIG. 4 depicts solvents used for dip coating PCL films.
Dichloromethane and ethyl acetate were both able to dissolve PCL at
high concentrations and to form uniform coatings with good
performance.
[0059] FIG. 5 depicts release rate profiles of M77 uncoated
formulation and M77 formulations with coatings of PCL only and PCL
with the addition of porogens (Water Soluble Polymers, WSPs)
Kollidon VA64 and Kolliphor RH40.
[0060] FIG. 6 depicts batch variability of release rate profiles of
M77 formulations with dip coatings of PCL only and PCL with the
addition of porogens (Kollidon VA64 and Kolliphor RH40)
[0061] FIG. 7 depicts the tuning effect of release rate profiles
for M77 formulations with dip coatings of PCL with the addition of
varying levels of porogens.
[0062] FIG. 8 depicts release rate profiles for formulations with
different levels of PEG 6000 in PCL coating.
[0063] FIG. 9A depicts release rate profiles for formulations with
increasing levels of TEC in PCL coating.
[0064] FIG. 9B depicts additional release rate profiles for
formulations with increasing levels of TEC in PCL coating.
[0065] FIG. 10A depicts release rate profiles for formulations with
varying ratios of PCL:copovidone and 10% or 30% triethyl citrate in
the coating.
[0066] FIG. 10B depicts additional release rate profiles for
formulations with varying ratios of PCL:copovidone and 10% or 30%
triethyl citrate in the coating.
[0067] FIG. 11 depicts the effects of low weight coating on drug
release rate, with varying ratios of PCL:copovidone and 10% or 30%
triethyl citrate in the coating.
[0068] FIG. 12 depicts the effect of ethyl cellulose coating on
consistent drug serum levels of Memantine HCl, compared to an
uncoated dosage form.
[0069] FIG. 13 depicts a near constant plasma drug concentrations
for dosage formulations with a PCL coating. The dosage forms
consisted of 90 A durometer polyurethane elastomers heat-welded to
M69 drug arms that were dip coated with a solution of 5% PCL w/v in
ethyl acetate.
[0070] FIG. 14 depicts a near constant plasma drug concentrations
for dosage formulations with a PCL coating. The dosage form
consisted of 60 A durometer LSR elastomers IR welded to 50/50
PCL/HPMAS disintegrating matrices and M77 drug arms that were
coated with a solution of 4.5% PCL/0.5% kollidon VA64 w/v in ethyl
acetate.
[0071] FIG. 15 depicts the linearity versus extent of release
comparison between coated drug formulations and those without
coating.
[0072] FIG. 16 depicts a comparison of pharmacokinetic parameters
for dosage forms consisting of 60 A durometer LSR elastomers IR
welded to 50/50 PCL/HPMAS disintegrating matrices and M77 drug arms
that were coated with a solution of 4.5% PCL/0.5% kollidon VA64 w/v
in ethyl acetate, versus a single dose of Namenda XR, a
commercially available extended release formulation of memantine.
The left chart shows the Namenda XR reference product single dose
variability, with C.sub.max (ng/mL) on the left axis and the left
grouping of points, and AUC (hr-ng/mL) on the right axis and the
right grouping of points. The right chart shows the dosage form
variability, with C.sub.max (ng/mL) on the left axis and the left
grouping of points, and AUC (hr-ng/mL) on the right axis and the
right grouping of points. Compared to the reference product, the
dosage form achieves nearly 7-fold higher AUC with a lower
C.sub.max and potentially lower inter-subject variability.
[0073] FIG. 17 depicts assays of formulations M105 and M106.
[0074] FIG. 18 shows the dissolution of uncoated M103, M104, M105
and M106 formulations in fasted-state simulated gastric fluid
(FaSSGF).
[0075] FIG. 19 shows the dissolution of M103 formulations with
various coatings (coatings C1, C2 versus uncoated).
[0076] FIG. 20 shows the dissolution of M104 formulations with
various coatings (coatings C1, C2 versus uncoated).
[0077] FIG. 21 shows the dissolution of M105 formulations with
various coatings (coatings C1, C2 versus uncoated).
[0078] FIG. 22 shows the dissolution of M104 formulations with
various coatings (coatings C3, C4 versus uncoated).
[0079] FIG. 23 shows the dissolution of M104 formulations with
various coatings (coatings C5, C6, C7 versus uncoated).
[0080] FIG. 24 shows the dissolution of M107 formulations with
various coatings (coatings C3, C4, C5 versus uncoated).
[0081] FIG. 25 shows the dissolution of M107 formulations with
various coatings (coatings C6, C7, C8 versus uncoated).
[0082] FIG. 26 shows percent release over time of donepezil from
formulations with various coatings (2.5% w/w and 5% w/w) versus
uncoated formulations.
[0083] FIG. 27 shows percent release over time of doxycycline from
formulations with various polycaprolactone-based coatings
("DX21-PCL" coatings) versus uncoated formulations.
[0084] FIG. 28 shows percent release over time of doxycycline from
formulations with various ethyl celluose-based coatings ("DX21-EC"
coatings) versus uncoated formulations.
[0085] FIG. 29 shows percent release over time of doxycycline from
formulations with various polycaprolactone-based coatings
("DX23-PCL" coatings) versus uncoated formulations.
[0086] FIG. 30 shows percent release over time of doxycycline from
formulations with various ethyl celluose-based coatings ("DX23-EC"
coatings) versus uncoated formulations.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0087] A "carrier polymer" is a polymer suitable for blending with
an agent, such as a drug, for use in the invention.
[0088] An "agent" is any substance intended for therapeutic,
diagnostic, or nutritional use in a patient, individual, or
subject. Agents include, but are not limited to, drugs, nutrients,
vitamins, and minerals.
[0089] A "dispersant" is defined as a substance which aids in the
minimization of particle size of agent and the dispersal of agent
particles in the carrier polymer matrix. That is, the dispersant
helps minimize or prevent aggregation or flocculation of particles
during fabrication of the systems. Thus, the dispersant has
anti-aggregant activity and anti-flocculant activity, and helps
maintain an even distribution of agent particles in the carrier
polymer matrix,
[0090] An "excipient" is any substance added to a formulation of an
agent that is not the agent itself. Excipients include, but are not
limited to, binders, coatings, diluents, disintegrants,
emulsifiers, flavorings, glidants, lubricants, and preservatives.
The specific category of dispersant falls within the more general
category of excipient.
[0091] An "elastic polymer" or "elastomer" (also referred to as a
"tensile polymer") is a polymer that is capable of being deformed
by an applied force from its original shape for a period of time,
and which then substantially returns to its original shape once the
applied force is removed.
[0092] A "coupling polymer" is a polymer suitable for coupling any
other polymers together, such as coupling a first carrier
polymer-agent component to a second carrier polymer-agent
component. Coupling polymers typically form the linker regions
between other components.
[0093] A "time-dependent polymer" or "time-dependent coupling
polymer" is a polymer that degrades in a time-dependent manner when
a gastric residence system is deployed in the stomach. A
time-dependent polymer is typically not affected by the normal pH
variations in the stomach.
[0094] "Approximately constant plasma level" refers to a plasma
level that remains within a factor of two of the average plasma
level (that is, between 50% and 200% of the average plasma level)
measured over the period that the gastric residence system is
resident in the stomach.
[0095] "Substantially constant plasma level" refers to a plasma
level that remains within plus-or-minus 25% of the average plasma
level measured over the period that the gastric residence system is
resident in the stomach.
[0096] A "hydrophilic therapeutic agent," "hydrophilic agent," or
"hydrophilic drug" is an agent which readily dissolves in water. A
hydrophilic agent is defined as an agent which has a solubility in
water of 1 mg/ml or greater. Alternatively, a hydrophilic agent can
be defined as an agent which has a log P.sub.oct (log partition
coefficient P.sub.oct, where P.sub.oct=(concentration in
1-octanol)/(concentration in H.sub.2O)) in a 1-octanol/water system
of less than 0.5. The pH at which solubility or log P.sub.oct is
measured is 1.6, approximating the gastric environment.
[0097] A "hydrophobic therapeutic agent," "hydrophobic agent," or
"hydrophobic drug" is an agent which does not readily dissolve in
water. A hydrophobic agent is defined as an agent which has a
solubility in water of less than 1 mg/ml. Alternatively, a
hydrophobic agent can be defined as an agent which has a log
P.sub.oct (log partition coefficient) in a 1-octanol/water system
of greater than 1. Alternatively, a hydrophobic therapeutic agent
can be defined as an agent which has a higher solubility in ethanol
than in water. Alternatively, a hydrophobic therapeutic agent can
be defined as an agent which has a higher solubility in 40%
ethanol/60% simulated gastric fluid than in 100% simulated gastric
fluid.
[0098] "Biocompatible," when used to describe a material or system,
indicates that the material or system does not provoke an adverse
reaction, or causes only minimal, tolerable adverse reactions, when
in contact with an organism, such as a human. In the context of the
gastric residence systems, biocompatibility is assessed in the
environment of the gastrointestinal tract.
[0099] A "patient," "individual," or "subject" refers to a mammal,
preferably a human or a domestic animal such as a dog or cat. In a
most preferred embodiment, a patient, individual, or subject is a
human.
[0100] The "diameter" of a particle as used herein refers to the
longest dimension of a particle.
[0101] "Treating" a disease or disorder with the systems and
methods disclosed herein is defined as administering one or more of
the systems disclosed herein to a patient in need thereof, with or
without additional agents, in order to reduce or eliminate either
the disease or disorder, or one or more symptoms of the disease or
disorder, or to retard the progression of the disease or disorder
or of one or more symptoms of the disease or disorder, or to reduce
the severity of the disease or disorder or of one or more symptoms
of the disease or disorder. "Suppression" of a disease or disorder
with the systems and methods disclosed herein is defined as
administering one or more of the systems disclosed herein to a
patient in need thereof, with or without additional agents, in
order to inhibit the clinical manifestation of the disease or
disorder, or to inhibit the manifestation of adverse symptoms of
the disease or disorder. The distinction between treatment and
suppression is that treatment occurs after adverse symptoms of the
disease or disorder are manifest in a patient, while suppression
occurs before adverse symptoms of the disease or disorder are
manifest in a patient. Suppression may be partial, substantially
total, or total. Because some diseases or disorders are inherited,
genetic screening can be used to identify patients at risk of the
disease or disorder. The systems and methods of the invention can
then be used to treat asymptomatic patients at risk of developing
the clinical symptoms of the disease or disorder, in order to
suppress the appearance of any adverse symptoms.
[0102] "Therapeutic use" of the systems disclosed herein is defined
as using one or more of the systems disclosed herein to treat a
disease or disorder, as defined above. A "therapeutically effective
amount" of a therapeutic agent, such as a drug, is an amount of the
agent, which, when administered to a patient, is sufficient to
reduce or eliminate either a disease or disorder or one or more
symptoms of a disease or disorder, or to retard the progression of
a disease or disorder or of one or more symptoms of a disease or
disorder, or to reduce the severity of a disease or disorder or of
one or more symptoms of a disease or disorder. A therapeutically
effective amount can be administered to a patient as a single dose,
or can be divided and administered as multiple doses.
[0103] "Prophylactic use" of the systems disclosed herein is
defined as using one or more of the systems disclosed herein to
suppress a disease or disorder, as defined above. A
"prophylactically effective amount" of an agent is an amount of the
agent, which, when administered to a patient, is sufficient to
suppress the clinical manifestation of a disease or disorder, or to
suppress the manifestation of adverse symptoms of a disease or
disorder. A prophylactically effective amount can be administered
to a patient as a single dose, or can be divided and administered
as multiple doses.
[0104] As used herein, the singular forms "a", "an", and "the"
include plural references unless indicated otherwise or the context
clearly dictates otherwise.
[0105] When numerical values are expressed herein using the term
"about" or the term "approximately," it is understood that both the
value specified, as well as values reasonably close to the value
specified, are included. For example, the description "about
50.degree. C." or "approximately 50.degree. C." includes both the
disclosure of 50.degree. C. itself, as well as values close to
50.degree. C. Thus, the phrases "about X" or "approximately X"
include a description of the value X itself. If a range is
indicated, such as "approximately 50.degree. C. to 60.degree. C."
or "about 50.degree. C. to 60.degree. C.," it is understood that
both the values specified by the endpoints are included, and that
values close to each endpoint or both endpoints are included for
each endpoint or both endpoints; that is, "approximately 50.degree.
C. to 60.degree. C." (or "about 50.degree. C. to 60.degree. C.") is
equivalent to reciting both "50.degree. C. to 60.degree. C." and
"approximately 50.degree. C. to approximately 60.degree. C." (or
"about 50.degree. C. to 60.degree. C.").
[0106] With respect to numerical ranges disclosed in the present
description, any disclosed upper limit for a component may be
combined with any disclosed lower limit for that component to
provide a range (provided that the upper limit is greater than the
lower limit with which it is to be combined). Each of these
combinations of disclosed upper and lower limits are explicitly
envisaged herein. For example, if ranges for the amount of a
particular component are given as 10% to 30%, 10% to 12%, and 15%
to 20%, the ranges 10% to 20% and 15% to 30% are also envisaged,
whereas the combination of a 15% lower limit and a 12% upper limit
is not possible and hence is not envisaged.
[0107] Unless otherwise specified, percentages of ingredients in
compositions are expressed as weight percent, or weight/weight
percent. It is understood that reference to relative weight
percentages in a composition assumes that the combined total weight
percentages of all components in the composition add up to 100. It
is further understood that relative weight percentages of one or
more components may be adjusted upwards or downwards such that the
weight percent of the components in the composition combine to a
total of 100, provided that the weight percent of any particular
component does not fall outside the limits of the range specified
for that component.
[0108] Partitioning behavior of an agent can be measured between a
polycaprolactone phase (PCL phase) and a simulated gastric fluid
phase (SGF phase), to give the partition coefficient P.sub.PCL-SGF
between the two phases for the agent. Log P.sub.PCL-SGF can also he
calculated. A 5:1 mixture of polycaprolactone diol (MW 530):ethyl
acetate can be used as the PCL phase, and fasted-state simulated
gastric fluid (FaSSGF) can be used as the SGF phase, such that
P.sub.PCL-SGF=(concentration in polycaprolactone
diol)/(concentration in FaSSGF)).
[0109] Some embodiments described herein are recited as
"comprising" or "comprises" with respect to their various elements.
In alternative embodiments, those elements can be recited with the
transitional phrase "consisting essentially of" or "consists
essentially of" as applied to those elements. In further
alternative embodiments, those elements can be recited with the
transitional phrase "consisting of" or "consists of" as applied to
those elements. Thus, for example, if a composition or method is
disclosed herein as comprising A and B, the alternative embodiment
for that composition or method of "consisting essentially of A and
B" and the alternative embodiment for that composition or method of
"consisting of A and B" are also considered to have been disclosed
herein. Likewise, embodiments recited as "consisting essentially
of" or "consisting of" with respect to their various elements can
also be recited as "comprising" as applied to those elements.
Finally, embodiments recited as "consisting essentially of" with
respect to their various elements can also be recited as
"consisting of" as applied to those elements, and embodiments
recited as "consisting of" with respect to their various elements
can also be recited as "consisting essentially of" as applied to
those elements.
[0110] When a composition or system is described as "consisting
essentially of" the listed elements, the composition or system
contains the elements expressly listed, and may contain other
elements which do not materially affect the condition being treated
(for compositions for treating conditions), or the properties of
the described system (for compositions comprising a system).
However, the composition or system either does not contain any
other elements which do materially affect the condition being
treated other than those elements expressly listed (for
compositions for treating systems) or does not contain any other
elements which do materially affect the properties of the system
(for compositions comprising a system); or, if the composition or
system does contain extra elements other than those listed which
may materially affect the condition being treated or the properties
of the system, the composition or system does not contain a
sufficient concentration or amount of those extra elements to
materially affect the condition being treated or the properties of
the system. When a method is described as "consisting essentially
of" the listed steps, the method contains the steps listed, and may
contain other steps that do not materially affect the condition
being treated by the method or the properties of the system
produced by the method, but the method does not contain any other
steps which materially affect the condition being treated or the
system produced other than those steps expressly listed.
[0111] This disclosure provides several embodiments. It is
contemplated that any features from any embodiment can be combined
with any features from any other embodiment where possible. In this
fashion, hybrid configurations of the disclosed features are within
the scope of the present invention.
[0112] In addition to the embodiments and methods disclosed here,
additional embodiments of gastric residence systems, and methods of
making and using such systems, are disclosed in International
Patent Application Nos. WO 2015/191920, WO 2015/191925, WO
2017/070612, WO 2017/100367, and PCT/US2017/034856, which are
incorporated by reference herein in their entirety.
Drug Polymer Formulations and Excipients for Gastric Residence
Systems
[0113] Selection of the carrier material for the agent or
pharmaceutically acceptable salt thereof in a gastric residence
system influences the release profile of drug during the period of
gastric residence, and is discussed in more detail below in the
section "Carrier polymers for segments and elongate members
(carrier polymer-agent component)." Release of drug can be
modulated by a wide variety of excipients included in the carrier
polymer-agent component. Soluble excipients include P407, Eudragit
E, PEG, Polyvinylpyrrolidone (PVP), and Polyvinyl alcohol (PVA).
Insoluble, wicking excipients include Eudragit RS and Eudragit RL.
Degradable excipients include PLA, PLGA, PLA-PCL, polydioxanone,
and linear copolymers of caprolactone and glycolide; polyaxial
block copolymers of glycolide, caprolactone, and trimethylene
carbonate; polyaxial block copolymers of glycolide, trimethylene
carbonate, and lactide; polyaxial block copolymers of glycolide,
trimethylene carbonate and polypropylene succinate; polyaxial block
copolymers of caprolactone, lactide, glycolide, and trimethylene
carbonate; polyaxial block copolymers of glycolide, trimethylene
carbonate, and caprolactone; and linear block copolymers of
lactide, caprolactone, and trimethylene carbonate; such as linear
copolymers of caprolactone (95%) and glycolide (5%); polyaxial
block copolymers of glycolide (68%), caprolactone (29%), and
trimethylene carbonate (3%); polyaxial block copolymers of
glycolide (86%), trimethylene carbonate (9%), and lactide (5%);
polyaxial block copolymers of glycolide (70%), trimethylene
carbonate (27%) and polypropylene succinate (2%), polyaxial block
copolymers of caprolactone (35%), lactide (34%), glycolide (17%),
and trimethylene carbonate (14%), polyaxial block copolymers of
glycolide (55%), trimethylene carbonate (25%), and caprolactone
(20%); and linear block copolymers of lactide (39%), caprolactone
(33%), and trimethylene carbonate (28%). Insoluble, swellable
excipients include Polyvinyl acetate (PVAc), Crospovidone,
Croscarmellose, HPMCAS, and linear block copolymers of dioxanone
and ethylene glycol; linear block copolymers of lactide and
ethylene glycol; linear block copolymers of lactide, ethylene
glycol, trimethyl carbonate, and caprolactone; linear block
copolymers of lactide, glycolide, and ethylene glycol; linear block
copolymers of glycolide, polyethylene glycol, and ethylene glycol;
such as linear block copolymers of dioxanone (80%) and ethylene
glycol (20%); linear block copolymers of lactide (60%) and ethylene
glycol (40%); linear block copolymers of lactide (68%), ethylene
glycol (20%), trimethyl carbonate (10%), and caprolactone (2%);
linear block copolymers of lactide (88%), glycolide (8%), and
ethylene glycol(4.degree. linear block copolymers of glycolide
(67%), polyethylene glycol (28%), and ethylene glycol (5%).
Surfactants include Lecithin, Taurocholate, SDS, Soluplus, Fatty
acids, and Kolliphor RH40.
Release Rate-Modulating Polymer Films
[0114] The current invention provides, inter alia, gastric
residence systems, elongate m embers s of gastric residence
systems, and segments for use in gastric residence systems and
elongate members of gastric residence systems, which are coated
with a release rate-modulating film. Use of a release
rate-modulating polymer film with the gastric residence systems,
such as on the carrier polymer-agent segments of the gastric
residence systems or on the elongate members of the gastric
residence systems, provides several significant advantages over
systems with carrier polymer-agent segments lacking a release
rate-modulating film. Release rate-modulating polymer films reduce
the burst release of agent upon initial contact with gastric fluid.
Linearity of agent release over the residence period is improved by
using release rate-modulating polymer films. Both of these
advantages provide better regulation of dosing from the gastric
residence systems. Sonic compositions of the release
rate-modulating polymer films can also significantly reduce burst
release upon exposure to alcohol, as compared to systems lacking
such films.
[0115] The release rate-modulating polymer films are coatings which
can coat all or part of a carrier polymer-agent segment. The films
can be continuous, discontinuous, flat, or textured. They can be a
smooth coating over a segment, or can follow contours of pores that
may be present on the surface of a segment.
[0116] in a preferred embodiment, the release rate modulating film
of any of the gastric residence systems disclosed herein does not
cover the coupling polymers, enteric polymers, enteric linkers,
time-dependent linkers, disintegrating polymers, disintegrating
matrices, or other linkers of the gastric residence system. If a
release-rate modulating polymer film is coated on the surface of an
elongate member which comprises one or more linkers, such as a
coupling polymer, enteric polymer, enteric linker, time-dependent
linker, disintegrating polymer, disintegrating matrix, or other
linker, the film is discontinuous and does not cover or coat the
linkers. This is readily accomplished by applying a release
rate-modulating film to segments which will comprise an elongate
member, and then linking the coated segments together with linkers
to form an elongate member; the segments comprising carrier
polymer-agent (or agent salt) will thus be coated with the release
rate-modulating film, but the linkers will not be coated with the
release rate-modulating film.
[0117] The films are typically applied to segments of the gastric
residence systems. The films can also be applied to multi-segment
elongate members prior to attachment of the multi-segment elongate
members to a central elastomer. The films can also be applied to
non-segmented elongate members (that is, elongate members which
comprise only one segment) prior to attachment of the non-segmented
elongate members to a central elastomer. The non-segmented elongate
member can be attached to the central elastomer either directly or
via a linker, such as a disintegrating matrix or coupling polymer.
An example of segments of a gastric residence system is shown in
FIG. 1A, where segment 102 and segment 103 are linked by linker
104, and attached to a central elastomer 106. The segments 102 and
104 comprise carrier polymer and agent (such as a drug). Using a
release rate-modulating polymer film on the segments of the gastric
residence system provides the advantageous characteristics
described herein.
[0118] Several parameters of the films can be adjusted in order to
generate desired agent release characteristics, and are discussed
below.
Chemical Composition of Release Rate-Modulating Polymer Films
[0119] Various polymers can be used to form the release-rate
modulating polymer films. Polyesters are a useful class of
compounds for preparation of release rate-modulating polymer films.
Polyesters that can be used in the invention include polyesters
with aliphatic groups as their main chains, including polylactones
such as polycaprolactone (PCL); polyglycolic acid (PGA); polylactic
acid (PLA); poly(lactic-co-glycolic acid) (PLGA);
polyhydroxyalkanoates (PHA) such as polyhydroxybutyrate (PHB),
polyhydroxyvalerate (PHV), and
poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV); polyethylene
adipate (PEA); polybutylene succinate (PBS); and polyesters with
aromatic groups in their main chains, such as polyethylene
terephthalate (PET), polybutylene terephthalate (PBT),
polytrimethylene terephthalate (PTT), and polyethylene naphthalate
(PEN). Heteropolymers, including block or random copolymers, such
as block or random copolymers incorporating the monomer
constituents of the above polyesters, can also be used, including
copolymers of lactide and caprolactone
(poly-lactide-co-caprolactone; PLC). Mixtures of two or more
polyesters can also be used.
[0120] In addition to polyesters, cellulose acetate (CA), ethyl
cellulose (EC), and copolymers of acrylate and methacrylate esters
(e.g., Eudragit RS) can also be used as release rate-modulating
polymer films.
[0121] Mixtures of polymers from two or more different chemical
classes of polymers can also be employed to form the release-rate
modulating polymer films.
[0122] Release rate modulating polymer films can comprise
polyesters with a repeating unit of the form:
--R.sup.1--O--C(.dbd.O)--
[0123] wherein R.sup.1 is selected from the group consisting of
C.sub.1-C.sub.12 alkylene groups, such as C.sub.1-C.sub.8 alkylene
groups or C.sub.1C.sub.4 alkylene groups, ethers containing between
two and twelve carbon atoms, two and eight carbon atoms or two and
four carbon atoms, and polyethers containing between three and
twelve carbon atoms or between three and eight carbon atoms. The
polyesters can terminate with hydroxy groups, hydrogens,
--C.sub.1--C12 alkyl groups, --C.sub.1-C.sub.8 alkyl groups, or
--C.sub.1-C.sub.4 alkyl groups, or --C.sub.1-C.sub.12--OH,
--C.sub.1-C.sub.8--OH, or --C.sub.1-C.sub.4--OH (alcohol) groups as
appropriate. In some embomdiments, the R.sup.1 groups can he the
same moiety throughout the polymer to form a homopolymer. In some
embodiments, the R.sup.1 groups can be chosen from two or more
different moieties, to form a heteropolymer. The heteropolymer can
he a random copolymer, or a block copolymer,
[0124] The release-rate modulating polymer film can comprise at
least two different polyesters, each different polyester with a
repeating unit of the form:
--R.sup.n--O--C(.dbd.O)--
[0125] wherein when at least two or more of the different
polyesters are homopolymers, the R.sup.n group of any one of the
homopolymers is different from the R.sup.n group of any other of
the homopolymers; and when at least two or more of the different
polyesters are heteropolymers, each heteropolymer has a different
varying pattern of R.sup.n groups than the varying pattern of
R.sup.n groups of any of the other heteropolymers; and each R.sup.n
is selected from the group consisting of C.sub.1-C.sub.12 alkylene
groups, ethers containing between two and twelve carbon atoms, and
polyethers containing between three and twelve carbon atoms.
[0126] Preferred polyesters for use as release rate-modulating
polymer films are polycaprolactone and polydioxanone, particularly
polycaprolactone (PCL). PCL having number-average molecular weight
of about 10,000 Mn to about 150,000 Mn; about 20,000 Mn to about
120,000 Mn; about 30,000 Mn to about 120,000 Mn; about 40,000 Mn to
about 120,000 Mn; about 50,000 Mn to about 110,000 Mn; about 80,000
to about 120,000 Mn; about 80,000 Mn to about 110,000 Mn, about
60,000 Mn to about 100,000 Mn; about 70,000 Mn to about 90,000 Mn;
about 80,000 Mn; about 90,000 Mn; about 100,000 Mn; about 10,000 Mn
to about 100,000 Mn; about 10,000 Mn to about 80,000 Mn; about
40,000 Mn to about 70,000 Mn; about 50,000 Mn to about 60,000 Mn;
or about 55,000 Mn can be used for release rate-modulating polymer
films. PCL of about 80,000 Mn to about 110,000 Mn is preferred,
such as about 85,000 Mn to 95,000 Mn, or about 90,000 Mn.
[0127] Polycaprolactone can also be characterized by its intrinsic
viscosity. PCL of about 1.0 dL/g to about 2.5 dL/g or about 1.5
dL/g to about 2.1 dL/g can be used. The intrinsic viscosity can be
measured in CHCl.sub.3 at 25.degree. C.
Porogens, plasticizers, and Other Additives to Release
Rate-Modulating Polymer Films
[0128] Porogens, plasticizers, or both porogens and plasticizers
can be added to the release rate-modulating polymer films to
further tune the release rate of the agent in the carrier
polymer-agent segment.
[0129] Porogens are soluble additives that dissolve out of the
release rate-modulating polymer films, creating pores in the films.
In some embodiments, the porogens dissolve out of the films when
the gastric residence systems are deployed in the gastric
environment. That is, after preparation of the segments, the
porogens are left in the segments which are assembled into the
gastric residence system, and in the gastric residence system as
administered to a patient; the porogens then dissolve out of the
release rate-modulating polymer film when the gastric residence
system is administered to the patient and contacts the gastric
environment. In another embodiment, the porogens are removed from
the film-covered carrier polymer-agent segments before the segments
are assembled into the gastric residence system, or the porogens
are removed from the gastric residence system before deployment of
the gastric residence system in the gastric environment.
[0130] Porogens can be organic or inorganic materials. Examples of
porogens include alkali metal salts such as sodium chloride, sodium
bromide, potassium chloride, potassium sulfate, potassium
phosphate, sodium benzoate, sodium acetate, sodium citrate,
potassium nitrate and the like; alkaline earth metal salts such as
calcium chloride, calcium nitrate, and the like; and transition
metal salts such as ferric chloride, ferrous sulfate, zinc sulfate,
cupric chloride, and the like. Additional examples of porogens
include saccharides and sugars, such as sucrose, glucose, fructose,
mannose, galactose, aldohexose, altrose, talose, lactose,
cellulose, monosaccharides, disaccharides, and water soluble
polysaccharides. Additional examples of porogens include sorbitol,
mannitol, organic aliphatic and aromatic oils, including diols and
polyols, as exemplified by polyhydric alcohols, poly(alkylene
glycols), polyglycols, alkylene glycols, poly(a,m)alkylenediol
esters or alkylene glycols, poly vinylalcohol, poly vinyl
pyrrolidone, and water soluble polymeric materials. Further
examples of porogens that can be used include Poloxamer;
hypromellose (HPMC); Kolliphor M40; polyvinyl caprolactam;
polyvinyl acetate (PVAc); polyethylene glycol (PEG); Soluplus
(available from BASF; a copolymer of polyvinyl caprolactam,
polyvinyl acetate, and polyethylene glycol); copovidone; Eudragits
(E, RS, RL); poly(methyl vinyl ether-alt-maleic anhydride);
polyoxyethylene alkyl ethers; polysorbates; polyoxyethylene
stearates; polydextrose; polyacrylic acid; alginates; sodium starch
glycolate (SSG); crosslinked polyactylic acid (carbopol);
crosslinked PVP (crospovidone); crosslinked cellulose
(croscarmellose); calcium silicate; xanthan gum; and gellan gum.
Some particularly useful porogens include povidone, copovidone, and
polyoxyl castor oil.
[0131] Porogens can be added to make up between about 1% to about
30% by weight of the release rate-modulating polymer film. Porogens
can be added to make up about 1% to about 25%. about 1% to about
20%, about 1% to about 15%, about 10% to about 10%, about 1% to
about 8%, about 1% to about 5%, about 1% to about 3%, about 5% to
about 30%, about 10% to about 30%, about 15% to about 30%, about
20% to about 30%, or about 25% to about 30% by weight of the
release rate-modulating polymer film. A preferred range of porogen
is about 5% to about 20%, more preferably about 10% to about 20%,
by weight of the release rate-modulating polymer film.
[0132] Plasticizers can also be added to further tune the
properties of the release rate-modulating polymer films.
Plasticizers that can be used include the classes of phthalates,
phosphates, citrates, tartrates, adipates, sebacates, sulfonamides,
succinates, glycolates, glycerolates, benzoates, myristates, and
halogenated phenyls. Specific plasticizers that can be used include
triacetin, triethyl citrate, PEG, poloxamer, tributyl citrate, and
dibutyl sebacate. Triacetin and triethyl citrate (TEC) are
particularly useful.
[0133] Plasticizers can be added to make up about 1% to about 35%,
about 1% to about 30%, about 1% to about 25%, about 1% to about
20%, about 1% to about 15%, about 1% to about 10%, about 1% to
about 8%, about 1% to about 5%, about 1% to about 3%, about 5% to
about 40%, about 10% to about 40%, about 15% to about 40%, about
20% to about 40%, about 25% to about 40%, about 30% to about 40%,
about 10% to about 30%, about 15% to about 30%, about 20% to about
30%, about 25% to about 30%, or about 10%, about 15%, about 20%,
about 25%, about 30%, about 35%, or about 40% by weight of the
release rate-modulating polymer film. A preferred range of
plasticizer is about 5% to about 20%, more preferably about 10% to
about 20%, by weight of the release rate-modulating polymer
film.
[0134] Processing aids can also be added to release rate-modulating
polymer films. Anti-tack agents, such as magnesium stearate, talc,
or glycerol monostearate can be added to aid in processing of the
films. Such anti-tack agents be added in amounts of about 0.5% to
about 5%, about 1% to about 3%, or about 2%.
Permeable Components in Release-Rate Modulating Polymer Films
[0135] The release-rate modulating polymer film can further
comprise a permeable component which is permeable to the agent or
pharmaceutically acceptable salt thereof, permeable to water, or
permeable both to the agent or salt thereof and to water.
Permeability components can thus function to increase the rate of
water influx into the carrier polymer of the gastric residence
system, and increase the rate of release of agent or salt thereof
out of the gastric residence system. The permeable component can he
a polymer or a swellable material. The permeable component can
comprise about 1% to about 30% by weight of the film. The permeable
component can be selected from the group consisting of SSG (sodium
starch glycolate), crospovidone, croscarmellose, and Carbopol (PAA;
crosslinked polyacrylic acid). At least one of the rate of passage
of water and the rate of passage of agent or salt thereof through
the permeable component should be higher, as compared to the rate
of passage of water or the rate of passage of agent through the
release-rate modulating polymer film lacking permeable agent and
lacking pores produced by removal of porogens. In various
embodiments, the rate of passage of water, the rate of passage of
agent or salt thereof, or both the rate of passage of water and the
rate of passage of agent or salt thereof through the permeable
component is up to about 1.5 times, up to about 2 times, up to
about 3 times, up to about 4 times, up to about 5 times, up to
about 6 times, up to about 7 times, up to about 8 times, about to
about 10 times, up to about 15 times, up to about 20 times, up to
about 25 times, up to about 50 times, or up to about 100 times
faster, as compared to the rate of passage of water or the rate of
passage of agent or salt thereof, or both the rate of passage of
water and the rate of passage of agent or salt thereof through the
release-rate modulating polymer film lacking permeable agent and
lacking pores produced by removal of porogens.
Film Combinations
[0136] Various options that can be used for the release
rate-modulating polymer film for segments and elongate members are
as follows (percentages are weight percentages):
[0137] Polymer used in film, about 40% to about 80%; porogen, about
3% to about 20%; plasticizer,about 3% to about 20%; anti-tack
agent, about 0.5% to about 5%;
[0138] Polymer used in film, about 50% to about 72%; porogen, about
5% to about 20%; plasticizer, about 5% to about 20%; anti-tack
agent, about 0.5% to about 5%; or
[0139] Polymer used in film, about 53% to about 65%; porogen, about
10% to about 20%; plasticizer, about 10% to about 20%; anti-tack
agent, about 1% to about 3%.
[0140] Examples of polymers that can be used in any of these
options are polycaprolactone and polydioxanone; preferably,
polycaprolactone is used as the polymer.
[0141] Examples of porogens that can be used in any of these
options are povidone, copovidone, and polyoxyl castor oil.
[0142] Examples of plasticizers that can be used in any of these
options include triethyl citrate, triacetin, PEG, poloxamer,
tributyl citrate, and dibutyl sebacate.
[0143] Examples of anti-tack agents that can be used in any of
these options include magnesium stearate, talc, and glycerol
monostearate.
[0144] A preferred combination for the release-rate modulating
polymer film is polycaprolactone, copovidone, triethyl citrate, and
Mg stearate.
[0145] Specific polymer-porogen-plasticizer-anti-tack agent
combinations that can be used include
polycaprolactone-povidone-triethyl citrate-Mg stearate;
polycaprolactone-copovidone-triethyl citrate-Mg stearate;
polycaprolactone-polyoxyl castor oil-triethyl citrate-Mg stearate;
polycaprolactone-povidone-triacetin-Mg stearate;
polycaprolactone-copovidone-triacetin-Mg stearate;
polycaprolactone-polyoxyl castor oil-triacetin-Mg stearate;
polycaprolactone-povidone-PEG-Mg stearate;
polycaprolactone-copovidone-PEG-Mg stearate;
polycaprolactone-polyoxyl castor oil-PEG-Mg stearate;
polycaprolactone-povidone-poloxamer-Mg stearate;
polycaprolactone-copovidone-poloxamer-Mg stearate;
polycaprolactone-polyoxyl castor oil-poloxamer-Mg stearate;
polycaprolactone-povidone-tributyl citrate-Mg stearate;
polycaprolactone-copovidone-tributyl citrate-Mg stearate;
polycaprolactone-polyoxyl castor oil-tributyl citrate-Mg stearate;
polycaprolactone-povidone-dibutyl sebacate-Mg stearate;
polycaprolactone-copovidone-dibutyl sebacate-Mg stearate;
polycaprolactone-polyoxyl castor oil-dibutyl sebacate-Mg stearate;
polycaprolactone-povidone-triethyl citrate-talc;
polycaprolactone-copovidone-triethyl citrate-talc;
polycaprolactone-polyoxyl castor oil-triethyl citrate-talc;
polycaprolactone-povidone-triacetin-talc;
polycaprolactone-copovidone-triacetin-talc;
polycaprolactone-polyoxyl castor oil-triacetin-talc;
polycaprolactone-povidone-PEG-talc;
polycaprolactone-copovidone-PEG-talc; polycaprolactone-polyoxyl
castor oil-PEG-talc; polycaprolactone-povidone-poloxamer-talc;
polycaprolactone-copovidone-poloxamer-talc;
polycaprolactone-polyoxyl castor oil-poloxamer-talc;
polycaprolactone-povidone-tributyl citrate-talc;
polycapmlactone-copovidone-tributyl citrate-talc;
polycaprolactone-polyoxyl castor oil-tributyl citrate-talc;
polycaprolactone-povidone-dibutyl sebacate-talc;
polycaprolactone-copovidone-dibutyl sebacate-talc;
polycaprolactone-polyoxyl castor oil-dibutyl sebacate-talc;
polycaprolactone-povidone-triethyl citrate-glycerol monostearate;
polycaprolactone-copovidone-triethyl citrate-glycerol monostearate;
polycaprolactone-polyoxyl castor oil-triethyl citrate-glycerol
monostearate; polycaprolactone-povidone-triacetin-glycerol
monostearate; polycaprolactone-copovidone-triacetin-glycerol
monostearate; polycaprolactone-polyoxyl castor
oil-triacetin-glycerol monostearate;
polycaprolactone-povidone-PEG-glycerol monostearate;
polycaprolactone-copovidone-PEG-glycerol monostearate;
polycaprolactone-polyoxyl castor oil-PEG-glycerol monostearate;
polycaprolactone-povidone-poloxamer-glycerol monostearate;
polycaprolactone-copovidone-poloxamer-glycerol monostearate;
polycaprolactone-polyoxyl castor oil-poloxamer-glycerol
monostearate; polycapmlactone-povidone-tributyl citrate-glycerol
monostearate; poiycaprolactone-copovidone-tributyl citrate-glycerol
monostearate; polycaprolactone-polyoxyl castor oil-tributyl
citrate-glycerol monostearate; polycaprolactone-povidone-dibutyl
sebacate-glycerol monostearate; polycaprolactone-copovidone-dibutyl
sebacate-glycerol monostearate; and polycaprolactone-polyoxyl
castor oil-dibutyl sebacate-glycerol monostearate.
[0146] In addition to the coatings listed above, any coating from
Table COAT-1 and Table COAT-2 may be used as a release
rate-modulating polymer film, for example in amounts of 1%, 1.5%,
2%, 2.5%, 3%, 3.5%, 4%, 4.5%, or 5% by weight of the elongate
member or segment to which they are applied. The coatings can be
used in any amount disclosed herein for the release-rate polymer
films, such as about 1% to about 20%. Each row of the table below
represents a coating formulation.
TABLE-US-00001 TABLE COAT-1 Coating Formulation Eudragit RS PCL 55k
Ethyl Cellulose 75:25 PLGA 50:50 PLGA 25:75 PLGA 50:50 PLGA Ethyl
Cellulose Cellulose Acetate PCL 55k PCL 15k PLGA 50:50 Ester
Terminated 35-45k PLGA 50:50 Acid Terminated 35-45k PCL 80k Ethyl
Cellulose Cp 10 Ethyl Cellulose Cp 10 Polycaprolactone, copovidone,
triethyl citrate, Mg stearate Ethyl Cellulose:PVP 1.3M PCL 80k:TEC
Ethyl Cellulose Cp10:TEC 80k PCL:PVP 80k PCL:Kolliphor RH40 80k
PCL:Kollidon VA64 PCL 80k:TEC Ethyl Cellulose Cp10:TEC PCL 55k:P407
PCL 55k:P188 PCL 55k:PEG 10k PCL 55k:PEG 100k PCL 55k:P407 PCL
55k:P188 PCL 55k:PVP 1M Ethyl Cellulose:PEG 1M Ethyl Cellulose:PEG
100k PCL 80k:TEC Ethyl Cellulose Cp10:TEC PVP 80k PCL:Kolliphor
RH40 80k PCL:Kollidon VA64
[0147] Table COAT-2 lists specific amounts of ingredients that can
he used in the film formulations. The amounts listed in Table
COAT-2 can be varied by plus-or-minus 20% of each ingredient (for
example, a composition with 10% P407 can vary between 8% P407 to
12% P407). The coatings can be used in any amount disclosed herein
for the release-rate polymer films, such as about 1% to about 20%.
Each row of the table below represents a coating formulation.
TABLE-US-00002 TABLE COAT-2 Coating Formulation 9:1, PCL 55k:P407
9:1, PCL 55k:P188 Eudragit RS 9:1 PCL 55k:PEG 10k 9:1 PCL 55k:PEG
100k PCL 55k 9:1, PCL 55k:P407 9:1, PCL 55k:P188 9:1 PCL 55k:PVP 1M
Ethyl Cellulose 9:1 Ethyl Cellulose:PVP 1.3M 9:1 Ethyl
Cellulose:PEG 1M 9:1 Ethyl Cellulose:PEG 100k 75:25 PLGA 25:75 PLGA
50:50 PLGA Ethyl Cellulose Cellulose Acetate 9:1 Ethyl
Cellulose:PEG 1M 9:1 Cellulose Acetate TEG 1M Cellulose Acetate PCL
55k PCL 15k PLGA 50:50 Ester Terminated 35-45k PLGA 50:50 Acid
Terminated 35-45k PCL 80k 9:1 PCL 80k:TEC 8:2 PCL 80k:TEC 7:3 PCL
80k:TEC Ethyl Cellulose Ethyl Cellulose Cp 10 9:1 Ethyl Cellulose
Cp10:TEC 8:2 Ethyl Cellulose Cp10:TEC 7:3 Ethyl Cellulose Cp10:TEC
7:3 80k PCL:PVP 9:1 PVP 7:3 80k PCL:Kolliphor RH40 9:1 80k
PCL:Kolliphor RH40 7:3 80k PCL:Kollidon VA64 9:1 80k PCL:Kollidon
VA64 polycaprolactone 83.8%, copovidone 4.4%, Triethyl citrate
9.%8, Magnesium stearate % 2.0 polycaprolactone 66.7%, copovidone
16.6%, Triethyl citrate 14.7%, Magnesium stearate 2.0%
polycaprolactone 48.0%, copovidone 20.6%, Triethyl citrate, 29.4%,
Magnesium stearate 2.0%, polycaprolactone 54.9%, copovidone 13.7%,
Triethyl citrate 29.4%, Magnesium stearate 2.0% polycaprolactone
54.9%, copovidone 23.5%, Triethyl citrate 19.6%, Magnesium stearate
2.0% polycaprolactone 62.7%, copovidone 15.7%, Triethyl citrate
19.6%, Magnesium stearate 2.0% polycaprolactone 62.5%, copovidone
20.8%, Triethyl citrate 14.7%, Magnesium stearate 2.0%
polycaprolactone 70.6%, copovidone 17.6%, Triethyl citrate 9.8%,
Magnesium stearate 2.0%
Film Thickness
[0148] The release-rate modulating polymer films should be very
thin in comparison to the carrier polymer-agent segment of the
gastric residence system that they cover. This allows for diffusion
of water into the carrier polymer-agent segment, and diffusion of
agent out of the segment.
[0149] The thickness of the release-rate modulating polymer films
can be between about 1 micrometer to about 40 micrometers, between
about 1 micrometer to about 30 micrometers, or between about 1
micrometer to about 25 micrometers. The films are typically between
about 1 micrometer to about 20 micrometers, such as between about 1
micrometer to about 20 micrometers, about 1 micrometer to about 15
micrometers, about 1 micrometer to about 10 micrometers, about 1
micrometer to about 5 micrometers, about 1 micrometer to about 4
micrometers, about 1 micrometer to about 3 micrometers, about 1
micrometer to about 2 micrometers, about 2 micrometers to about 10
micrometers, about 5 micrometers to about 20 micrometers, about 5
micrometer to about 10 micrometers, about 10 micrometer to about 15
micrometers, or about 15 micrometers to about 20 micrometers.
[0150] In further embodiments, the release-rate modulating polymer
film does not add substantially to the strength of the carrier
polymer-agent segment that it covers. In further embodiments, the
release-rate modulating polymer film adds less than about 20%, less
than about 10%, less than about 5%, or less than about 1% to the
strength of the segment. The strength of the segment can be
measured by the four-point betiding flexural test (ASTM D790)
described in Example 18 of WO 2017/070612 and Example 13 of WO
2017/100367.
Film Weight
[0151] The release-rate modulating polymer films can make up about
0,1% to 20% of the weight of the film-covered carrier polymer-agent
segment of the gastric residence system. The release-rate
modulating polymer films can make up about 0.1% to 15% of the
weight of the film-covered carrier polymer-agent segment of the
gastric residence system. The release-rate modulating polymer films
can make up about 0.1% to 10% of the weight of the film-covered
carrier polymer-agent segment of the gastric residence system. The
weight of the film can make up about 0.1% to about 8%, about 0.1%
to about 5%, about 0.1% to about 4%, about 0.1% to about 3%, about
0.1% to about 2%, about 0.1% to about 1%, about 0.5% to about 10%,
about 0.5% to about 8%, about 0.5% to about 5%, about 0.5% to about
4%, about 0.5% to about 3%, about 0.5% to about 2%, about 0.5% to
about 1%, about 1% to about 10%, about 1% to about 8%, about 1% to
about 5%, about 1% to about 4%, about 1% to about 3%, or about 1%
to about 2% of the film-covered carrier polymer-agent segment of
the gastric residence system.
Application of Release Rate-Modulating Polymer Films onto Segments
for Use in Gastric Residence Systems
[0152] The release rate-modulating polymer films can be applied to
segments for use in gastric residence systems using various
techniques. Several of the techniques involve coating a segment,
comprising a carrier polymer and agent, with a solution of a
formulation of a release rate-modulating polymer film, producing a
film-coated segment. The film-coated segment is then dried.
[0153] Various methods of coating films onto objects are known in
the art, and include dip coating, pan coating, spray coating, and
fluidized bed coating. Fluidized bed coating is also known as
Wurster coating or air suspension coating. For these coating
methods, a formulation of a release-rate modulating polymer film,
including the polymer, and any porogens and plasticizers if
present, is prepared as a solution. The solvent used for the
solution of the polymer film formulation is typically an organic
solvent, such as ethyl acetate, dichloromethane, acetone, methanol,
ethanol, isopropanol, or any combination thereof. Preferably, Class
3 solvents as listed in the guidance from the United States Food
and Drug Administration at URL
www.fda.gov/downloads/drugs/guidances/ucm073395.pdf (which include
ethanol, acetone, and ethyl acetate) are used; however, Class 2
solvents (which include dichloromethane and. methanol) can be used
if necessary for the formulation. Class 1 and Class 4 solvents
should be used only when the formulation cannot be prepared with a
suitable Class 3 or Class 2 solvent.
[0154] Release rate-modulating polymer films can also be integrated
onto segments by co-extrusion, where the segment formulation is
co-extruded with a surrounding thin layer of the release
rate-modulating polymer film.
[0155] The Examples below illustrate the use of some of these
coating techniques for preparation of segments with a release
rate-modulating polymer film.
Overall System Configuration
[0156] The current invention provides, inter alia, gastric
residence systems, elongate members of gastric residence systems,
and segments for use in gastric residence systems and elongate
members of gastric residence systems, which are coated with a
release rate-modulating film. As discussed, the release
rate-modulating film provides a number of advantages.
[0157] Gastric residence systems can be prepared in different
configurations. The "stellate" configuration of a gastric residence
system is also known as a "star" (or "asterisk") configuration. An
example of a stellate system 100 is shown schematically in FIG. 1A.
Multiple elongate members, or "arms" (only one such arm, 108, is
labeled for clarity), are affixed to disk-shaped central elastomer
106. The elongate members or arms depicted in FIG. 1A are comprised
of segments 102 and 103, joined by a coupling polymer or linker
region 104 (again, the components are only labeled in one arm for
clarity) which serves as a linker region. This configuration
permits the system to be folded or compacted at the central
elastomer. FIG. 1B shows a folded configuration 190 of the gastric
residence system of FIG. 1A (for clarity, only two arms are
illustrated in FIG. 1B). Segments 192 and 193, linker region 194,
elastomer 196, and arm 198 of FIG. 1B correspond to segments 102
and 103, linker region 104, elastomer 106, and arm 108 of FIG. 1A,
respectively. When folded, the overall length of the system is
reduced by approximately a factor of two, and the system can be
conveniently placed in a container such as a capsule or other
container suitable for oral administration. When the capsule
reaches the stomach, the capsule dissolves, releasing the gastric
residence system. The gastric residence system then unfolds into
its uncompacted state, which is retained in the stomach for the
desired residence period.
[0158] While the linker regions 104 are shown as slightly larger in
diameter than the segments 102 and 103 in FIG. 1A, they can be the
same diameter as the segments, so that the entire elongate member
102-104-103 has a smooth outer surface.
[0159] In some embodiments, the stellate system may have an
elongate member or arm composed of only one segment, which is
attached to the central elastomer by a linker region. This
corresponds to FIG. 1A with the segments 103 omitted. The
single-segment elongate members comprising segments 102 are then
directly attached to central elastomer 106 via the linkers 104. The
linkers can comprise a coupling polymer or a disintegrating
matrix.
[0160] A stellate system can be described as a gastric residence
system for administration to the stomach of a patient, comprising
an elastomer component, and a plurality of at least three carrier
polymer-agent components comprising a carrier polymer and an agent
or a salt thereof, attached to the elastomer component, wherein
each of the plurality of carrier polymer-agent components is an
elongate member comprising a proximal end, a distal end, and an
outer surface therebetween; wherein the proximal end of each
elongate member is attached to the elastomer component and projects
radially from the elastomer component, each elongate member having
its distal end not attached to the elastomer component and located
at a larger radial distance from the elastomer component than the
proximal end; wherein each elongate member independently comprises
one or more segments, each segment comprising a proximal end, a
distal end, and an outer surface therebetween; and wherein, when
two or more segments are present in an elongate member, each
segment is attached to an adjacent segment via a linker region. The
linker region can be a coupling polymer or a disintegrating matrix.
The elongate members can be attached to the central elastomer via a
coupling polymer or a disintegrating matrix, and can have
intervening portions of interfacing polymers. For the plurality of
at least three elongate members, or for a plurality of elongate
members, a preferred number of elongate members is six, but three,
four, five, seven, eight, nine, or ten elongate members can be
used. The elongate members should be equally spaced around the
central elastomer; if there are N elongate members, there will be
an angle of about 360/N degrees between neighboring elongate
members.
[0161] FIG. 1C shows another possible overall configuration 120 for
a gastric residence system, which is a ring configuration. Segments
122 are joined by coupling polymer or linker region 124 (only one
segment and one coupling linkage are labeled for clarity). The
coupling polymer/linker region in this design must also function as
an elastomer, to enable the ring to be twisted into a compacted
state for placement in a container, such as a capsule.
[0162] In one embodiment of the stellate configuration, the
segments 102 and 103 comprise a carrier polymer blended with an
agent or drug. In one embodiment of the ring configuration, the
segments 122 comprise a carrier polymer blended with an agent or
drug.
[0163] The coupling polymers of the gastric residence system, which
serve as linker regions, are designed to break down gradually in a
controlled manner during the residence period of the system in the
stomach. If the gastric residence system passes prematurely into
the small intestine in an intact form, the system is designed to
break down much more rapidly to avoid intestinal obstruction. This
is readily accomplished by using enteric polymers as coupling
polymers. Enteric polymers are relatively resistant to the acidic
pH levels encountered in the stomach, but dissolve rapidly at the
higher pH levels found in the duodenum. Use of enteric coupling
polymers as safety elements protects against undesired passage of
the intact gastric residence system into the small intestine. The
use of enteric coupling polymers also provides a manner of removing
the gastric residence system prior to its designed residence time;
should the system need to be removed, the patient can drink a
mildly alkaline solution, such as a sodium bicarbonate solution, or
take an antacid preparation such as hydrated magnesium hydroxide
(milk of magnesia) or calcium carbonate, which will raise the pH
level in the stomach and cause rapid degradation of the enteric
coupling polymers. The gastric residence system will then break
apart and be eliminated from the patient. In the system shown in
FIG. 1A, at least the coupling polymer used for the couplings 104
are made from such enteric polymers.
[0164] In additional embodiments, a time-dependent coupling polymer
or linker can be used. Such a time-dependent coupling polymer or
linker degrades in a predictable, time-dependent manner. In some
embodiments, the degradation of the time-dependent coupling polymer
or linker may not be affected by the varying pH of the
gastrointestinal system.
[0165] In additional embodiments, different types of linkers can be
used in the gastric residence systems. That is, both enteric
linkers (or enteric coupling polymers) and time-dependent linkers
(or time-dependent coupling polymers) can be used. In some
embodiments, a single multi-segment elongate member arm of a
stellate system can use both an enteric linker at some linker
regions between segments, and a time-dependent linker at other
linker regions between segments.
[0166] Linker regions are typically about 100 microns to about 1
millimeter in width, such as about 200 um to about 1000 um, about
300 um to about 1000 tun, about 400 um to about 1000 um, about 500
um to about 1000 um, about 600 um to about 1000 um, about 700 um to
about 1000 um, about 800 um to about 1000 um, or about 900 um to
about 1000 um; or about 100 um to about 900 um about 100 um to
about 800 um, about 100 um to about 700 um, about 100 um to about
600 um, about 100 um to about 500 um, about 100 um to about 400 um,
about 100 um to about 300 um, or about 100 um to about 200 um.
Linker regions can be about 100 um, about 200 um, about 300 um,
about 400 um, about 500 um, about 600 um, about 700 um, about 800
um, about 900 um, or about 1000 um in width, where each value can
be plus or minus 50 um (.+-.50 um).
[0167] The central elastomeric polymer of a stellate system is
typically not an enteric polymer; however, the central elastomeric
polymer can also be made from such an enteric polymer where
desirable and practical.
[0168] The central elastomer should have a specific durometer and
compression set. The durometer is important because it determines
the folding force of the dosage form and whether it will remain in
the stomach; a preferred range is from about 60 to about 90 A. The
compression set should be as low as possible to avoid having
permanent deformation of the gastric residence system when stored
in the capsule in its compacted configuration. A preferred range is
about 10% to about 20% range. Materials that fit these requirements
are the QP1 range of liquid silicone rubbers from Dow Corning. In
any embodiment with a central elastomer, the QP1-270 (70 A
durometer) liquid silicone rubber can be used.
[0169] Segments and elongate members of the gastric residence
systems can have cross-sections in the shape of a circle (in which
case the segments are cylindrical), a polygon (such as segments
with a triangular cross-section, rectangular cross-section, or
square cross-section), or a pie-shaped cross-section (in which case
the segments are cylindrical sections). Segments with
polygon-shaped or pie-shaped cross-sections, and ends of
cylindrically-shaped sections which will come into contact with
gastric tissue, can have their sharp edges rounded off to provide
rounded corners and edges, for enhanced safety in vivo. That is,
instead of having a sharp transition between intersecting edges or
planes, an arc is used to transition from one edge or plane to
another edge or plane. Thus, a "triangular cross-section" includes
cross-sections with an approximately triangular shape, such as a
triangle with rounded corners. An arm with a triangular
cross-section includes an arm where the edges are rounded, and the
corners at the end of the arm are rounded. Rounded corners and
edges are also referred to as fillet corners, filleted corners,
fillet edges, or filleted edges.
[0170] As discussed herein, the segments of the gastric residence
system, comprising carrier polymer and agent, can be covered with a
release rate-modulating polymer film. In some embodiments, one or
more of any coupling polymer, disintegrating matrix, or interfacing
polymer affixed to the segments are also covered by the release
rate-modulating polymer film. In some embodiments, one or more of
any coupling polymer, disintegrating matrix, or interfacing polymer
affixed to the segments arc not covered by the release
rate-modulating polymer film. If the coupling polymer (which may be
an enteric polymer) or the disintegrating matrix is covered by the
release rate-modulating polymer film, the kinetics of de-coupling
or disintegration should be determined on the film-covered coupling
polymer or the film-covered disintegrating matrix.
Evaluation of Release Characteristics
[0171] The release characteristics of agent from segments, elongate
members, and gastric residence systems can be evaluated by various
assays. Assays for agent release arc described in detail in the
examples. Release of agent in vitro from segments, elongate
members, and gastric residence systems can be measured by immersing
a segment, elongate member, or gastric residence system in a
liquid, such as water, 0.1N HCl, fasted state simulated gastric
fluid (FaSSGF), or fed state simulated gastric fluid (FeSSGF).
Fasted state simulated gastric fluid (FaSSGF) is preferred for
release assays. Simulated gastric fluid indicates either fasted
state simulated gastric fluid (FaSSGF) or fed state simulated
gastric fluid (FeSSGF); when a limitation is specified as being
measured in simulated gastric fluid (SGF), the limitation is met if
the limitation holds in either fasted state simulated gastric fluid
(FaSSGF) or fed state simulated gastric fluid (FeSSGF). For
example, if a segment is indicated as releasing at least 10% of an
agent over the first 24 hours in simulated gastric fluid, the
limitation is met if the segment releases at least 10% of the agent
over the first 24 hours in fasted state simulated gastric fluid, or
if the segment releases at least 10% of the agent over the first 24
hours in fed state simulated gastric fluid.
[0172] Ethanol burst release is typically measured by immersing a
segment, elongate member, or gastric residence system in a solution
of 40% ethanol and 60% fasted state simulated gastric fluid for one
hour, followed by immersing the same segment, elongate member, or
gastric residence system in 100% fasted state simulated gastric
fluid for the remainder of the test period, and measuring release
of agent at appropriate time points. This test is designed to
simulate the effects of consumption of alcoholic beverages by a
patient having a gastric residence system of the invention deployed
in the patient's stomach.
[0173] While in vitro tests can be performed using segments,
elongate members, or gastric residence systems, use of segments for
in vitro tests is most convenient for rapid evaluation of the
release characteristics. When in vitro tests are done to compare
release rates under different conditions (such as release in 100%
FaSSGF versus release in 40% ethanol/60% FaSSGF), the comparison
solutions are kept at the same temperature, such as room
temperature, 25.degree. C., or 37.degree. C. Room temperature
(ambient temperature) is a preferred temperature for comparisons;
in one embodiment, the ambient temperature does not drop below
20.degree. C. or exceed 25.degree. C. (although it may fluctuate
between 20.degree. C. and 25.degree. C.).
[0174] In vivo tests can be performed in animals such as dogs (for
example, beagle dogs or hound dogs) and swine. For in vivo tests, a
gastric residence system is used, since an individual segment or
elongate member would not be retained in the stomach of the animal.
Blood samples can he obtained at appropriate time points, and, if
desired, gastric contents can be sampled by cannula or other
technique.
[0175] Clinical trials in humans, conducted in accordance with
appropriate laws, regulations, and institutional guidelines, also
provide in vivo data.
Release Profiles
[0176] The increased linearity profiles of the segments with
release rate-modulating polymer films provides advantageous release
characteristics over a segment with the same carrier polymer-agent
composition, but lacking the release rate-modulating polymer films.
For example, a segment of a gastric residence system comprising a
carrier polymer, an agent or a salt thereof, and a release-rate
modulating polymer film configured to control the release rate of
the agent, can have a release profile where the release-rate
modulating polymer film is configured such that, over a seven-day
incubation in simulated gastric fluid, the amount of the agent or
salt thereof released during day 5 is at least about 40% of the
amount of agent or salt thereof released during day 2. That is,
over the seven day incubation period, the amount of the agent or
salt thereof released from hours 96-120 (day 5) is at least about
40% of the amount of agent or salt released during hours 24-48 (day
2) of the incubation. In some embodiments, release over day 5 is at
least about 50%, at least about 60%, at least about 70%, at least
about 80%, or at least about 90% of the amount of agent or salt
released over day 2. In some embodiments, release over day 5 is at
least about 40% to about 90%, at least about 50% to about 90%, at
least about 60% to about 90%, at least about 70% to about 90%, at
least about 80% to about 90%, or at least about 40% to about 100%,
of the amount of agent or salt released over day 2, in any of these
embodiments, at least about 5% of the total amount of agent is
released on day 2 and at least about 5% of the total amount of
agent is released on day 5, at least about 5% of the total amount
of agent is released on day 2 and at least about 7% of the total
amount of agent is released on day 5, or at least about 7% of the
total amount of agent is released on day 2 and at least about 7% of
the total amount of agent is released on day 5. "Total amount of
agent" refers to the amount of agent originally present in the
segment.
[0177] In another embodiment, a segment of a gastric residence
system comprising a carrier polymer, an agent or a salt thereof,
and a release-rate modulating polymer film configured to control
the release rate of the agent, can have a release profile where the
release-rate modulating polymer film is configured such that, over
a seven-day incubation in simulated gastric fluid, the amount of
the agent or salt thereof released during day 7 is at least about
20% of the amount of agent or salt thereof released during day 1.
That is, over the seven day incubation period, the amount of the
agent or salt thereof released from hours 144-168 (day 7) is at
least about 20% of the amount of agent or salt released during
hours0-24 (day 1) of the incubation, in some embodiments, release
over day 7 is at least about 30%, at least about 40%, at least
about 50%, at least about 60%, or at least about 70% of the amount
of agent or salt released over day 1. In some embodiments, release
over day 7 is at least about 20% to about 70%, at least about 30%
to about 70%, at least about 40% to about 70%, at least about 50%
to about 70%, at least about 60% to about 70%, or at least about
20% to about 100%, of the amount of agent or salt released over day
1. In any of these embodiments, at least about 7% of the total
amount of agent is released on day 1 and at least about 4% of the
total amount of agent is released on day 7, at least about 4% of
the total amount of agent is released on day 1 and at least about
4% of the total amount of agent is released on day 7, or at least
about 7% of the total amount of agent is released on day I and at
least about 7% of the total amount of agent is released on day 7.
"Total amount of agent" refers to the amount of agent originally
present in the segment.
[0178] Segments with release rate-modulating polymer films of the
invention also have lower burst release when initially immersed in
simulated gastric fluid. In one embodiment, a segment of a gastric
residence system comprising a carrier polymer and an agent or a
salt thereof, where the segment has a release-rate modulating
polymer film configured to control the release rate of the agent,
can have a release profile where the release-rate modulating
polymer film is configured such that the release of agent from the
segment in simulated gastric fluid over an initial 24 hour period
is at least about 40% lower than the release of agent from a second
segment in simulated gastric fluid over an initial 6 hour period,
where the second segment comprises the same combination of carrier
polymer and agent or salt thereof, but lacks the release-rate
modulating polymer film; and wherein the release of agent from the
segment with the polymer film in simulated gastric fluid over a
seven-day period is either i) at least about 60% of the release of
agent from the second segment lacking the polymer film over a
seven-day period, or ii) at least 60% of the total amount of agent
originally present in the segment. In further embodiments, the
release of agent from the segment with the film in simulated
gastric fluid over an initial 24 hour period is at least about 40%
lower, about 40% to about 50% lower, about 40% to about 60% lower,
or about 40% to about70% lower than the release of agent from a
second segment without the film in simulated gastric fluid over an
initial 6 hour period, while the release of agent from the segment
with the film in simulated gastric fluid over a seven day period is
either i) at least about 60%, at least about 70%, at least about
80%, or about 60% to about 80% of the release of agent from the
second segment in simulated gastric fluid lacking the polymer film
over a seven-day period, or ii) at least about 60%, at least about
70%, at least about 80%, or about 60% to about 80% of the total
amount of agent originally present in the segment. In further
embodiments, the release of agent from the segment with the film in
simulated gastric fluid over a seven-day period is either i) at
least about 60%, at least about 70%, at least about 75%, or at
least about 80% (such as about 60% to about 70%, about 60% to about
80%, about 60% to about 90%, or about 60% to about 99%) of the
release of agent from the second segment without the film in
simulated gastric fluid over a seven-day period, or ii) at least
about 60%, at least about 70%, at least about 75%, or at least
about 80% (such as about 60% to about 70%, about 60% to about 80%,
about 60% to about 90%, or about 60% to about 99%) of the total
amount of agent originally present in the segment.
[0179] Segments with release rate-modulating polymer films of the
invention also have lower burst release in an ethanol challenge as
compared to segments lacking the films. In one embodiment, a
segment of a gastric residence system comprising a carrier polymer
and an agent or a salt thereof, where the segment has a
release-rate modulating polymer film configured to control the
release rate of the agent, can have a release profile where the
release-rate modulating polymer film is configured such that the
release of agent from the segment in 40% ethanol/60% simulated
gastric fluid over one hour is at least about 40% lower than the
release of agent from a second segment in 40% ethanol/60% simulated
gastric fluid over one hour, the second segment comprising the same
combination of carrier polymer and agent or salt thereof but
lacking the release-rate modulating polymer film. In further
embodiments, the release of agent from the segment with the film in
simulated gastric fluid over a seven-day period is either i) at
least about 60%, at least about 70%, at least about 75%, or at
least about 80% (such as about 60% to about 70%, about 60% to about
80%, about 60% to about 90%, or about 60% to about 99%) of the
release of agent from the second segment without the film in
simulated gastric fluid over a seven-day period, or ii) i) at least
about 60%, at least about 70%, at least about 75%, or at least
about 80% (such as about 60% to about 70%, about 60% to about 80%,
about 60% to about 90%, or about 60% to about 99%) of the total
amount of agent originally present in the segment. In one
embodiment, a segment of a gastric residence system comprising a
carrier polymer and an agent or a salt thereof, where the segment
has a release-rate modulating polymer film configured to control
the release rate of the agent, can have a release profile where the
release-rate modulating polymer film is configured such that the
release of agent from the segment in 40% ethanol/60% simulated
gastric fluid over one hour is no more than about 40% higher
compared to release of agent from an equivalent segment in 100%
simulated gastric fluid over one hour. In further embodiments, the
release of agent from the segment with the film in simulated
gastric fluid over a seven-day period is either i) at least about
60%, at least about 70%, at least about 75%, or at least about 80%
(such as about 60% to about 70%, about 60% to about 80%, about 60%
to about 90%, or about 60% to about 99%) of the release of agent
from the second segment without the film in simulated gastric fluid
over a seven-day period, or ii) at least about 60%, at least about
70%, at least about 75%, or at least about 80% (such as about 60%
to about 70%, about 60% to about 80%, about 60% to about 90%, or
about 60% to about 99%) of the total amount of agent originally
present in the segment.
[0180] Linearity of release of agent from segments having a release
rate-modulating polymer fihn coating is also improved. In one
embodiment, a segment of a gastric residence system comprising a
carrier polymer and an agent or a salt thereof, where the segment
has a release-rate modulating polymer film configured to control
the release rate of the agent, can have a release profile where the
release-rate modulating polymer film is configured such that a
best-fit linear regression model of the release rate of agent has a
coefficient of determination R.sup.2 of at least about 0.8, at
least about 0.85, or at least about 0.9 over an initial period of
seven days in simulated gastric fluid (where the initial period of
seven days is measured from the start time when the segment is
initially immersed in simulated gastric fluid; that is, the period
of seven days includes the time at t=0 or origin point of the
release profile); and wherein the segment releases about 30% to
about 70% of the agent or salt thereof within a time of about 40%
to about 60% of the seven-day period.
[0181] In one embodiment, a segment of a gastric residence system
comprising a carrier polymer and an agent or a salt thereof, where
the segment has a release-rate modulating polymer film configured
to control the release rate of the agent, can have a release
profile where the release-rate modulating polymer film is
configured such that the release rate over any one of the seven
days varies by no more than about 50%, no more than about 40%, no
more than about 30%, no more than about 25%, no more than about
20%, or no more than about 10% from the average daily total release
over the seven days.
Carrier Polymers for Segments and Elongate Members (Carrier
Polymer-Agent Component)
[0182] The segments and elongate members of the gastric residence
system comprise a carrier polymer-agent component, which comprises
the agent (or a pharmaceutically acceptable salt of an agent) to be
eluted from the gastric residence system in the gastric
environment. The agent is blended into the carrier polymer to form
a carrier polymer-agent mixture. This mixture can be formed into
the desired shape or shapes for use as carrier polymer-agent
components in the systems. After the drug or drug salt is blended
into the carrier polymer to fomi the carrier polymer-drug mixture,
the drug or drug salt is distributed or dispersed throughout the
blended mixture. If excipients, anti-oxidants, or other ingredients
are included in the carrier polymer-drug blend, they will also be
distributed or dispersed throughout the blended mixture.
[0183] Preferably, carrier polymers have the following
characteristics. They should be thermoplastic, to allow extrusion
using hot melt extrusion or 3D printing techniques. They should
also have a high enough melt strength and viscosity to enable
extrusion into the required geometry. They should have low melting
temperatures (for example, less than about 120.degree. C.), to
avoid exposing agents or drugs to high temperatures during
manufacture. They should have sufficient mechanical strength
(Young's modulus, compression strength, tensile strength) to avoid
breaking in the stomach during the desired residence period. They
should be capable of forming stable blends with agents, therapeutic
agents, drugs, excipients, dispersants, and other additives.
[0184] Exemplary carrier polymers suitable for use in this
invention include, but are not limited to, hydrophilic cellulose
derivatives (such as hydroxypropylmethyl cellulose, hydroxypropyl
cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose,
carboxymethylcellulose, sodium-carboxymethylcellulose), cellulose
acetate phthalate, poly(vinyl pyrrolidone), ethylene/vinyl alcohol
copolymer, poly(vinyl alcohol), carboxyvinyl polymer (Carbomer),
Carbopol.RTM. acidic carboxy polymer, polycarbophil,
poly(ethyleneoxide) (Polyox WSR), polysaccharides and their
derivatives, polyalkylene oxides, polyethylene glycols, chitosan,
alginates, pectins, acacia, tragacanth, guar gum, locust bean gum,
vinylpyrrolidonevinyl acetate copolymer, dextrans, natural gum,
agar, agarose, sodium alginate, carrageenan, fucoidan, furcellaran,
laminaran, hypnea, eucheuma, gum arabic, gum ghatti, gum karaya,
arbinoglactan, amylopectin, gelatin, gellan, hyaluronic acid,
pullulan, scleroglucan, xanthan, xyloglucan, maleic anhydride
copolymers, ethylenemaleic anhydride copolymer, poly(hydroxyethyl
methacrylate), ammoniomethacrylate copolymers (such as Eudragit RL
or Eudragit RS), poly(ethylacrylate-methylmethacrylate) (Eudragit
NE), Eudragit E (cationic copolymer based on dimethylamino ethyl
methylacrylate and neutral methylacrylic acid esters), poly(acrylic
acid), polymethacrylates/polyethacrylates such as poly(methacrylic
acid), methylmethacrylates, and ethyl acrylates, polylactones such
as poly(caprolactone), polyanhydrides such as
poly[bis-(p-carboxyphenoxy)-propane anhydride], poly(terephthalic
acid anhydride), polypeptides such as polylysine, polyglutatnic
acid, poly(ortho esters) such as copolymers of DETOSU with diols
such as hexane diol, decane diol, cyclohexanedimethanol, ethylene
glycol, polyethylene glycol and incorporated herein by reference
those poly(ortho) esters described and disclosed in U.S. Pat. No.
4,304,767, starch, in particular pregelatinized starch, and
starch-based polymers, carbomer, maltodextrins, amylomaltodextrins,
dextrans, poly(2-ethyl-2-oxazoline), poly(ethyleneimine),
polyurethane, poly(lactic acid), poly(glycolic acid),
poly(lactic-co-glycolic acid) (PLGA), polyhydroxyalkanoates,
polyhydroxybutyrate, and copolymers, mixtures, blends and
combinations thereof. Polycaprolactone (PCL) is a preferred carrier
polymer. In another embodiment, polydioxanone is used as the
carrier polymer. In any of the embodiments of the gastric residence
system, the carrier polymer used in the gastric residence system
can comprise polycaprolactone, such as linear polycaprolactone with
a number-average molecular weight (Mn) range between about 60
kiloDalton (kDa) to about 100 kDa; 75 kDa to 85 kDa; or about 80
kDa; or between about 45 kDa to about 55 kDa; or between about 50
kDa to about 110,000 kDa, or between about 80 kDa to about 110,000
kDa.
[0185] Other excipients can be added to the carrier polymers to
modulate the release of agent. Such excipients can be added in
amounts from about 1% to 15%, preferably from about 5% to 10%, more
preferably about 5% or about 10%. Examples of such excipients
include Poloxamer 407 (available as Kolliphor P407, Sigma Cat #
62035), poly(ethylene glycol)-block-poly(propylene
glycol)-block-poly(ethylene glycol), CAS No. 9003-11-6;
H--(OCH2CH2)x-(O--CH(CH3)CH2)y-(OCH2CH2)z-OH where x and z are
about 101 and y is about 56); Pluronic P407, Eudragit E, Eudragit
EPO (available from Evonik); hypromellose (available from Sigma,
Cat # H3785), Kolliphor RH40 (available from Sigma, Cat # 07076),
polyvinyl caprolactam, polyvinyl acetate (PVAc),
polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyethylene
glycol (PEG), and Soluplus (available from BASF; a copolymer of
polyvinyl caprolactam, polyvinyl acetate, and polyethylene glycol).
Preferred soluble excipients include Eudragit E, polyethylene
glycol (PEG), polyvinylpyrrolidone (PVP), polyvinyl acetate (PVAc),
and polyvinyl alcohol (PVA). Preferred insoluble excipients include
Eudragit RS and Eudragit RL. Preferred insoluble, swellable
excipients include crospovidone, croscarmellose, hypromellose
acetate succinate (HPMCAS), and carbopol. EUDRAGIT RS and EUDRAGIT
RL are registered trademarks of Evonik (Darmstadt, Germany) for
copolymers of ethyl acrylate, methyl methacrylate and methacrylic
acid ester with quaternary ammonium groups (trimethylammonioethyl
methacrylate chloride), having a molar ratio of ethyl acrylate,
methyl methacrylate and trimethylammonioethyl methacrylate of about
1:2:0.2 in Eudragit.RTM. RL and about 1:2:0.1 in Eudragit.RTM. RS.
Preferred insoluble, swellable excipients include crospovidone,
croscarmellose, hypromellose acetate succinate (HPMCAS), carbopol,
and linear block copolymers of dioxanone and ethylene glycol;
linear block copolymers of lactide and ethylene glycol; linear
block copolymers of lactide, ethylene glycol, trimethyl carbonate,
and caprolactone; linear block copolymers of lactide, glycolide,
and ethylene glycol; linear block copolymers of glycolide,
polyethylene glycol, and ethylene glycol; such as linear block
copolymers of dioxanone (80%) and ethylene glycol (20%); linear
block copolymers of lactide (60%) and ethylene glycol (40%); linear
block copolymers of lactide (68%), ethylene glycol (20%), trimethyl
carbonate (10%), and caprolactone (2%); linear block copolymers of
lactide (88%), glycolide (8%), and ethylene glycol (4%); linear
block copolymers of glycolide (67%), polyethylene glycol (28%), and
ethylene glycol (5%).
[0186] Further examples of excipients that can be used in the
segments of the gastric residence system are listed in the
Excipient Table below.
TABLE-US-00003 Excipient Table Function General examples Specific
examples Polymeric and non-polymeric Polyalkylene oxides Kolliphor
RH, Kolliphor P407, solubilizers Polyethoxylated castor oil
Soluplus, Cremophor, SDS Detergents Release-enhancing excipient
Acrylate polymers Eudragit RL (porogen or wicking agent) Acrylate
co-polymers Eudragit RS Polyvinylpyrrolidone Eudragit E Linear
block copolymer of dioxanone and ethylene glycol (e.g., 80:20
ratio) Dispersant porous inorganic material silica,
hydrophilic-fumed silica, polar inorganic material hydrophobic
colloidal silica, non-toxic metal oxides magnesium aluminum
silicate, amphiphilic organic molecules stearate salts, calcium
stearate, polysaccharides, cellulose, cellulose magnesium stearate,
derivatives microcrystalline cellulose, fatty acids
carboxymethylcellulose, detergents hypromellose, phospholipids,
polyoxyethylene stearates, zinc acetate, alginic acid, lecithin,
sodium lauryl sulfate, aluminum oxide Stabilizer/Preservative agent
Anti-oxidants Tocopherols Anti-microbial agents Alpha-tocopherol
Buffering substances/ Ascorbic acid; ascorbate salts pH stabilizers
Carotenes Butylated hydroxytoluene (BHT) Butylated hydroxyanisole
(BHA) Fumaric acid calcium carbonate calcium lactate calcium
phosphate sodium phosphate sodium bicarbonate
Agents for Use in Gastric Residence Systems
[0187] Agents which can be administered to or via the
gastrointestinal tract can be used in the gastric residence systems
of the invention. The agent is blended with the carrier polymer,
and any other excipients or other additives to the carrier polymer,
and formed into a segment for use in a gastric residence system.
Agents include, but are not limited to, drugs, pro-drugs,
biologics, and any other substance which can be administered to
produce a beneficial effect on an illness or injury. Agents that
can be used in the gastric residence systems of the invention
include statins, such as rosuvastatin; nonsteroidal
anti-inflammatory drugs (NSAIDs) such as meloxicam; selective
serotonin reuptake inhibitors (SSRIs) such as escitalopram and
citalopram; blood thinners, such as clopidogrel; steroids, such as
prednisone; antipsychotics, such as aripiprazole and risperidone;
analgesics, such as buprenorphine; opioid antagonists, such as
naloxone; anti-asthmatics such as montelukast; anti-dementia drugs,
such as memantine; cardiac glycosides such as digoxin; alpha
blockers such as tamsulosin; cholesterol absorption inhibitors such
as ezetimibe; anti-gout treatments, such as colchicine,
antihistamines, such as loratadine and cetirizine, opioids, such as
loperamide; proton-pump inhibitors, such as omeprazole;, antiviral
agents, such as entecavir; antibiotics, such as doxycycline,
ciprofloxacin, and azithromycin; antimalarial agents;
levothyroxine; substance abuse treatments, such as methadone and
varenicline; contraceptives; stimulants, such as caffeine; and
nutrients such as folic acid, calcium, iodine, iron, zinc,
thiamine, niacin, vitamin C, vitamin D, biotin, plant extracts,
phytohormones, and other vitamins or minerals. Biologics that can
be used as agents in the gastric residence systems of the invention
include proteins, polypeptides, polynucleotides, and hormones.
Exemplary classes of agents include, but are not limited to,
analgesics; anti-analgesics; anti-inflammatory drugs; antipyretics;
antidepressants; antiepileptics; antipsychotic agents;
neuroprotective agents; anti-proliferatives, such as anti-cancer
agents; antihistamines; antimigraine drugs; hormones;
prostaglandins; antimicrobials, such as antibiotics, antifungals,
antivirals, and antiparasitics; anti-muscarinics; anxiolytics;
bacteriostatics; immunosuppressant agents; sedatives; hypnotics;
antipsychotics; bronchodilators; anti-asthma drugs; cardiovascular
drugs; anesthetics; anti-coagulants; enzyme inhibitors; steroidal
agents; steroidal or non-steroidal anti-inflammatory agents;
corticosteroids; dopaminergics; electrolytes; gastro-intestinal
drugs; muscle relaxants; nutritional agents; vitamins;
parasympathomimetics; stimulants; anorectics; anti-narcoleptics;
and antimalarial drugs, such as quinine, lumefantrine, chloroquine,
amodiaquine, pyrimethamine, proguanil, chlorproguanil-dapsone,
sulfonamides (such as sulfadoxine and sulfamethoxypyridazine),
mefloquine, atovaquone, primaquine, halofantrine, doxycycline,
clindamycin, artemisinin, and artemisinin derivatives (such as
artemether, dihydroartemisinin, arteether and artesunate). The term
"agent" includes salts, solvates, polymorphs, and co-crystals of
the aforementioned substances. In certain embodiments, the agent is
selected from the group consisting of cetirizine, rosuvastatin,
escitalopram, citalopram, risperidone, olanzapine, donepezil, and
ivermectin. In another embodiment, the agent is one that is used to
treat a neuropsychiatric disorder, such as an anti-psychotic agent
or an anti-dementia drug such as memantine.
[0188] In sonic embodiments of the invention disclosed herein, the
agent can exclude adamantane-class drugs. In some embodiments of
the invention disclosed herein, the agent can exclude any one or
more of memantine; amantadine; adapromine; nitromemantine;
rimantadine; bromantane; neramexane; or tromantadine; or a
pharmaceutically acceptable salt of memantine, amantadine,
adapromine, nitromemantine, rimantadine, bromantane, or
tromantadine. In some embodiments of the invention disclosed
herein, the agent can exclude memantine. In some embodiments of the
invention disclosed herein, the agent can exclude a salt of
memantine or a pharmaceutically acceptable salt of memantine.
Crystalline and Amorphous Forms of Agents
[0189] Agents can he used in the gastric residence systems of the
invention in any suitable crystalline form, or in amorphous form,
or in both crystalline form or forms and amorphous forms. That is,
agent or drug particles contained in the gastric residence systems
can be used in crystalline form, in amorphous form, or in a mixture
of crystalline forms (either a single crystalline form, or multiple
crystalline forms) and amorphous forms, so as to provide a desired
rate of release or desired physical or chemical properties.
Agent Classes of Interest
[0190] Gastric residence systems are well-suited for use in
treatment of diseases and disorders which present difficulties with
patient compliance, and thus in some embodiments, the gastric
residence systems are used to treat a disease or disorder where
patient compliance with a medication regimen is problematic. Such
diseases and disorders include neuropsychiatric diseases and
disorders, dementia and other diseases and disorders which affect
memory, Alzheimer's disease, psychoses, schizophrenia, and
paranoia. Accordingly, agents which can be used in the gastric
residence systems include, but are not limited to, anti-dementia
agents, anti-Alzheimer's disease agents, and anti-psychotics.
Hydrophilic Agents
[0191] Exemplary hydrophilic agents which can be used in the
systems include risperidone, cetirizine, memantine, and
olanzapine.
Hydrophobic Agents
[0192] Exemplary hydrophobic agents which can be used in the
systems include aripiprazole, ivermectin, rosuvastatin, citalopram,
and escitalopram.
Agent Loading of Elongate Members and Segments
[0193] The elongate members, or segments of which the elongate
members are comprised, comprise agent or a pharmaceutically
acceptable salt thereof. In some embodiments, the agent or salt
thereof (for example, a drug) makes up about 10% to about 40% by
weight of the elongate member or segment, and thus the carrier
polymer and any other components of the elongate member or segment
blended into the carrier polymer together make up the remainder of
the weight of the elongate member or segment. In some embodiments,
the agent or salt thereof makes up about 10% to about 35%, about
10% to about 30%, about 10% to about 25%, about 10% to about 20%,
about 10% to about 15%, about 15% to about 40%, about 20% to about
40%, about 25% to about 40%, about 30% to about 40%, about 35% to
about 40%, about 15% to about 35%, about 20% to about 35%, or about
25% to about 40% by weight of the elongate member or segment.
[0194] Further embodiments of elongate members or segments, where
the agent or salt thereof makes up more than about 40% by weight of
the elongate member or segment, are described below under "high
agent loading of elongate members and segments."
High Agent Loading of Elongate Members and Segments
[0195] In sonic embodiments of the invention, the elongate members,
or segments of which the elongate members are comprised, can have a
high loading of agent or pharmaceutically acceptable salt thereof
"High loading" generally refers to elongate members or segments
where the agent or salt thereof (for example, a drug) makes up more
than about 40% by weight of the elongate member or segment, and
thus the carrier polymer and any other components of the elongate
member or segment blended into the carrier polymer together make up
less than about 60% by weight of the elongate member or segment.
Any components of the elongate members or segments which are not
blended into the carrier polymer are not included in the
calculation of the weight percentage; for example, if an elongate
member has one or more disintegrating matrices interspersed between
segments of the elongate member, the weight of such matrices would
not be included as part of the weight of the elongate member in the
calculation of the weight percentage of agent in the elongate
member. Once the loading of the agent increases to about 60%, it
becomes increasingly difficult to properly blend the agent with the
carrier polymer, and phase separation of the agent and polymer
tends to occur. Thus, the loading of the agent in an elongate
member or segment should not exceed about 60% of the total weight
of the elongate member.
[0196] Thus, in some embodiments, the amount of agent by weight in
the elongate members, or segments of which the elongate members are
comprised, can comprise at least about 40%, at least about 45%, at
least about 50%, at least about 55%, or about 60%. In some
embodiments, the amount of agent by weight in the elongate members,
or segments of which the elongate members are comprised, can
comprise about 40% to about 60%, about 45% to about 60%, about 50%
to about 60%, about 55% to about 60%, about 40% to about 55%, about
40% to about 50%, or about 40% to about 45%. In some embodiments,
the amount of agent by weight in the elongate members, or segments
of which the elongate members are comprised, can comprise about 25%
to about 60%, about 30% to about 60%, or about 35% to about 60%. In
some embodiments, the amount of agent by weight in the elongate
members, or segments of which the elongate members are comprised,
can comprise about 51% to about 60%, about 52% to about 60%, about
53% to about 60%, about 54% to about 60%, about 55% to about 60%,
about 56% to about 60%, or about 57% to about 60%. In some
embodiments, the agent or pharmaceutically acceptable salt thereof
is present in an amount by weight of between about 67% and about
150% of the weight of the carrier polymer.
[0197] The combination of the high agent or agent salt loading with
the release rate-controlling polymer film provides gastric
residence systems with increased amounts of agent or agent salt,
while maintaining good release kinetics over the residence period
of the system.
[0198] The release-rate modulating polymer films can also be used
with loadings lower than the high-loading values above, such as an
amount of agent by weight in the elongate members, or segments of
which the elongate members are comprised, of about 20% to about
35%. Loading ranges covering both high-loading and
lower-than-high-loading can be used, such as between about 20% to
about 60%, between about 25% to about 60%, between about 30% to
about 60%, between about 35% to about 60%, between about 20% to
about 50%, between about 20% to about 40%, or between about 25% to
about 50%.
Dispersants for Modulation of Agent Release and Stability of
Polymer Blend
[0199] The use of a dispersant in the carrier polymer-agent
component provides numerous advantages. The rate of elution of
agent from the carrier polymer-agent component is affected by
numerous factors as previously noted, including the composition and
properties of the carrier polymer (which may itself comprise
multiple polymeric and non-polymeric components); the physical and
chemical properties of the agent; and the gastric environment.
Avoiding burst release of agent, especially hydrophilic agents, and
maintaining sustained release of the agent over the effective
release period or residence period is an important characteristic
of the systems. The use of a dispersant according to the invention
enables better control of release rate and suppression of burst
release. Burst release and release rate can be tuned by using
varied concentrations of dispersant. For example, different
dispersants and different excipients, at varying concentrations,
can tune burst release of cetirizine in simulated gastric
fluid.
[0200] Dispersants which can be used in the invention include:
silicon dioxide (silica, SiO.sub.2) (hydrophilic fumed); stearate
salts, such as calcium stearate and magnesium stearate;
microcrystalline cellulose; carboxymethylcellulose; hydrophobic
colloidal silica; hypromellose; magnesium aluminum silicate;
phospholipids; polyoxyethylene stearates; zinc acetate; alginic
acid; lecithin; fatty acids; sodium lauryl sulfate; and non-toxic
metal oxides such as aluminum oxide. Porous inorganic materials and
polar inorganic materials can be used. Hydrophilic-fumed silicon
dioxide is a preferred dispersant. One particularly useful silicon
dioxide is sold by Cabot Corporation (Boston, Mass., USA) under the
registered trademark CAB-O-SIL.RTM. M-5P (CAS# 112945-52-5), which
is hydrophilic-fumed silicon dioxide having a BET surface area of
about 200 m2/g.+-.15 m2/g The mesh residue for this product on a 45
micron sieve is less than about 0.02%. The typical primary
aggregate size is about 150 to about 300 nm, while individual
particle sizes may range from about 5 nm to about 50 nm.
[0201] In addition to anti-aggregation/anti-flocculation activity,
the dispersant can help prevent phase separation during fabrication
and/or storage of the systems. This is particularly useful for
manufacture of the systems by hot melt extrusion.
[0202] The weight/weight ratio of dispersant to agent substance can
be about 0.1% to about 5%, about 0.1% to about 4%, about 0.1% to
about 3%, about 0.1% to about 2%, about 0.1% to about 1%, about 1%
to about 5%, about 1% to about 4%, about 1% to about 3%, about 1%
to about 2%, about 2% to about 4%, about 2% to about 3%, about 3%
to about 4%, about 4% to about 5%, or about 0.1%, about 0.5%, about
1%, about 2%, about 3%, about 4% or about 5%.
[0203] Dispersants can comprise about 0.1% to about 4% of the
carrier polymer-agent components, such as about 0.1% to about 3.5%,
about 0.1% to about 3%, about 0.1% to about 2.5%, about 0.1% to
about 2%, about 0.1% to about 15%, about 0.1%, to about 1%, about
0.1% to about 0.5%, or about 0.2% to about 0.8%.
[0204] Dispersants can also be used to modulate the amount of burst
release of agent or pharmaceutically acceptable salt thereof during
the initial period when the gastric residence system is
administered. In embodiments of a gastric residence system that is
to be administered once weekly, the burst release over the
approximately first six hours after initial administration is less
than about 8%, preferably less than about 6%, of the total amount
of agent (or salt thereof) in the system. In embodiments of a
gastric residence system that is to be administered once every
three days, the burst release over the approximately first six
hours after initial administration is less than about 12%,
preferably less than about 10%, of the total amount of agent (or
salt thereof) in the system. In embodiments of a gastric residence
system that is to be administered once daily, the burst release
over the approximately first six hours after initial administration
is less than about 40%, preferably less than about 30%, of the
total amount of agent (or salt thereof) in the system. In general,
if a new gastric residence system is administered every D days, and
the total mass of agent (or salt thereof) is M, then the gastric
residence system releases less than about [(M divided by D) times
0.5], preferably less than about [(M divided by D) multiplied by
0.4], or less than about [(M divided by D) multiplied by 3/8], more
preferably less than about [(M divided by D) multiplied by 0.3],
over the approximately first six hours after initial
administration. In further embodiments, the gastric residence
system releases at least about [(M divided by D) multiplied by
0.25] over the approximately first six hours after initial
administration, that is, the system releases at least about
one-quarter of the daily dosage over the first one-quarter of the
first day of administration.
Stabilizers for Use in Gastric Residence Systems
[0205] Many agents are prone to oxidative degradation when exposed
to reactive oxygen species, which can be present in the stomach. An
agent contained in the system may thus oxidize due to the prolonged
residence in the stomach of the system, and the extended release
period of agent from the system. Accordingly, it is desirable to
include stabilizers or preservatives in the systems, in order to
stabilize the agent to prevent oxidative and other degradation.
[0206] Stabilizers, such as anti-oxidants including tocopherols,
alpha-tocopherol, ascorbic acid, ascorbyl palmitate, butylated
hydroxytoluene, butylated hydroxyanisole, and fumaric acid, can
comprise about 0.1% to about 4% of the carrier polymer-agent
components, such as about 0.1% to about 3.5%, about 0.1% to about
3%, about 0.1% to about 2.5%, about 0.1% to about 2%, about 0.1% to
about 1.5%, about 0.1% to about 1%, about 0.1% to about 0.5%, or
about 0.2% to about 0.8%.
[0207] Anti-oxidant stabilizers that can be included in the systems
to reduce or prevent oxidation of the agent include
alpha-tocopherol (about 0.01 to about 0.05% v/v), ascorbic acid
(about 0.01 to about 0.1% w/v), ascorbyl palmitate (about 0.01 to
about 0.1% w/v), butylated hydroxytoluene (about 0.01 to about 0.1%
w/w), butylated hydroxyanisole (about 0.01 to about 0.1% w/w), and
fumaric acid (up to 3600 ppm). Vitamin E, a tocopherol, a Vitamin E
ester, a tocopherol ester, ascorbic acid, or a carotene, such as
alpha-tocopherol, Vitamin E succinate, alpha-tocopherol succinate,
Vitamin E acetate, alpha-tocopherol acetate, Vitamin E nicotinate,
alpha-tocopherol nicotinate, Vitamin E linoleate, or
alpha-tocopherol linoleate can be used as anti-oxidant
stabilizers.
[0208] Certain agents can be pH-sensitive, especially at the low pH
present in the gastric environment. Buffering or pH-stabilizer
compounds that can be included in the systems to reduce or prevent
degradation of agent at low pH include calcium carbonate, calcium
lactate, calcium phosphate, sodium phosphate, and sodium
bicarbonate. They are typically used in an amount of up to about 2%
w/w. The buffering or pH-stabilizer compounds can comprise about
0.1% to about 4% of the carrier polymer-agent components, such as
about 0,1% to about 3.5%, about 0.1% to about 3%, about 0.1% to
about 2.5%, about 0.1% to about 2%, about 0.1% to about 1.5%, about
0.1% to about 1%, about 0.1% to about 0.5%, or about 0.2% to about
0.8%.
[0209] The anti-oxidant stabilizers, pH stabilizers, and other
stabilizer compounds are blended into the polymers containing the
agent (or pharmaceutically acceptable salt thereof) by blending the
stabilizer(s) into the molten carrier polymer-agent or agent salt
mixture. The stabilizer(s) can be blended into molten carrier
polymer prior to blending the agent (or salt thereof) into the
polymer-stabilizer mixture; or the stabilizer(s) can be blended
with agent (or salt thereof) prior to formulation of the blended
agent (or salt thereof)-stabilizer mixture in the carrier polymer;
or stabilizer(s), agent (or salt thereof), and molten carrier
polymer can be blended simultaneously. Agent (or salt thereof) can
also be blended with molten carrier polymer prior to blending the
stabilizer(s) into the polymer-agent or agent salt mixture.
[0210] In one embodiment, less than about 10% of the agent (or salt
thereof) remaining in the system is degraded or oxidized after a
gastric residence period of about 24 hours. In one embodiment, less
than about 10% of the agent (or salt thereof) remaining in the
system is degraded or oxidized after a gastric residence period of
about 48 hours. In one embodiment, less than about 10% of the agent
(or salt thereof) remaining in the system is degraded or oxidized
after a gastric residence period of about 72 hours. In one
embodiment, less than about 10% of the agent (or salt thereof)
remaining in the system is degraded or oxidized after a gastric
residence period of about 96 hours. In one embodiment, less than
about 10% of the agent (or salt thereof) remaining in the system is
degraded or oxidized after a gastric residence period of about five
days. In some embodiments, less than about 10% of the agent (or
salt thereof) remaining in the system is degraded or oxidized after
a gastric residence period of about a week. In some embodiments,
less than about 10% of the agent (or salt thereof) remaining in the
system is degraded or oxidized after a gastric residence period of
about two weeks.
[0211] In one embodiment, less than about 5% of the agent (or salt
thereof) remaining in the system is degraded or oxidized after a
gastric residence period of about 24 hours. In one embodiment, less
than about 5% of the agent (or salt thereof) remaining in the
system is degraded or oxidized after a gastric residence period of
about 48 hours. In one embodiment, less than about 5% of the agent
(or salt thereof) remaining in the system is degraded or oxidized
after a gastric residence period of about 72 hours. In one
embodiment, less than about 5% of the agent (or salt thereof)
remaining in the system is degraded or oxidized after a gastric
residence period of about 96 hours. In one embodiment, less than
about 5% of the agent (or salt thereof) remaining in the system is
degraded or oxidized after a gastric residence period of about five
days. In some embodiments, less than about 5% of the agent (or salt
thereof) remaining in the system is degraded or oxidized after a
gastric residence period of about a week. In some embodiments, less
than about 5% of the agent (or salt thereof) remaining in the
system is degraded or oxidized after a gastric residence period of
about two weeks.
Residence Time
[0212] The residence time of the gastric residence system is
defined as the time between administration of the system to the
stomach and exit of the system from the stomach. In one embodiment,
the gastric residence system has a residence time of about 24
hours, or up to about 24 hours. In one embodiment, the gastric
residence system has a residence time of about 48 hours, or up to
about 48 hours. In one embodiment, the gastric residence system has
a residence time of about 72 hours, or up to about 72 hours. In one
embodiment, the gastric residence system has a residence time of
about 96 hours, or up to about 96 hours, in one embodiment, the
gastric residence system has a residence time of about 5 days, or
up to about 5 days. In one embodiment, the gastric residence system
has a residence time of about 6 days, or up to about 6 days. In one
embodiment, the gastric residence system has a residence time of
about 7 days (about one week), or up to about 7 days (about one
week). In one embodiment, the gastric residence system has a
residence time of about 10 days, or up to about 10 days. In one
embodiment, the gastric residence system has a residence time of
about 14 days (about two weeks), or up to about 14 days (about two
weeks).
[0213] In one embodiment, the gastric residence system has a
residence time between about 24 hours and about 7 days. In one
embodiment, the gastric residence system has a residence time
between about 48 hours and about 7 days. In one embodiment, the
gastric residence system has a residence time between about 72
hours and about 7 days. In one embodiment, the gastric residence
system has a residence time between about 96 hours and about 7
days, In one embodiment, the gastric residence system has a
residence time between about 5 days and about 7 days. In one
embodiment, the gastric residence system has a residence time
between about 6 days and about 7 days.
[0214] In one embodiment, the gastric residence system has a
residence time between about 24 hours and about 10 days. In one
embodiment, the gastric residence system has a residence time
between about 48 hours and about 10 days. In one embodiment, the
gastric residence system has a residence time between about 72
hours and about 10 days. In one embodiment, the gastric residence
system has a residence time between about 96 hours and about 10
days. In one embodiment, the gastric residence system has a
residence time between about 5 days and about 10 days. In one
embodiment, the gastric residence system has a residence time
between about 6 days and about 10 days. In one embodiment, the
gastric residence system has a residence time between about 7 days
and about 10 days.
[0215] In one embodiment, the gastric residence system has a
residence time between about 24 hours and about 14 days. In one
embodiment, the gastric residence system has a residence time
between about 48 hours and about 14 days. In one embodiment, the
gastric residence system has a residence time between about 72
hours and about 14 days. In one embodiment, the gastric residence
system has a residence time between about 96 hours and about 14
days. In one embodiment, the gastric residence system has a
residence time between about 5 days and about 14 days. In one
embodiment, the gastric residence system has a residence time
between about 6 days and about 14 days. In one embodiment, the
gastric residence system has a residence time between about 7 days
and about 14 days. In one embodiment, the gastric residence system
has a residence time between about 10 days and about 14 days.
[0216] The gastric residence system releases a therapeutically
effective amount of agent (or salt thereof) during at least a
portion of the residence time or residence period during which the
system resides in the stomach. In one embodiment, the system
releases a therapeutically effective amount of agent (or salt
thereof) during at least about 25% of the residence time. In one
embodiment, the system releases a therapeutically effective amount
of agent (or salt thereof) during at least about 50% of the
residence time. In one embodiment, the system releases a
therapeutically effective amount of agent (or salt thereof) during
at least about 60% of the residence time. In one embodiment, the
system releases a therapeutically effective amount of agent (or
salt thereof) during at least about 70% of the residence time. In
one embodiment, the system releases a therapeutically effective
amount of agent (or salt thereof) during at least about 75% of the
residence time. In one embodiment, the system releases a
therapeutically effective amount of agent (or salt thereof) during
at least about 80% of the residence time, in one embodiment, the
system releases a therapeutically effective amount of agent (or
salt thereof) during at least about 85% of the residence time. In
one embodiment, the system releases a therapeutically effective
amount of agent (or salt thereof) during at least about 90% of the
residence time. In one embodiment, the system releases a
therapeutically effective amount of agent (or salt thereof) during
at least about 95% of the residence time. In one embodiment, the
system releases a therapeutically effective amount of agent (or
salt thereof) during at least about 98% of the residence time. In
one embodiment, the system releases a therapeutically effective
amount of agent (or salt thereof) during at least about 99% of the
residence time.
Radiopacity
[0217] The systems are optionally radiopaque, so that they can be
located via abdominal X-ray if necessary. In some embodiments, one
or more of the materials used for construction of the system is
sufficiently radiopaque for X-ray visualization. In other
embodiments, a radiopaque substance is added to one or more
materials of the system, or coated onto one or more materials of
the system, or are added to a small portion of the system. Examples
of suitable radiopaque substances are barium sulfate, bismuth
subcarbonate, bismuth oxychloride, and bismuth trioxide. It is
preferable that these materials should not be blended into the
polymers used to construct the gastric residence system, so as not
to alter drug release from the carrier polymer, or desired
properties of other system polymers. Metal striping or tips on a
small portion of the system components can also be used, such as
tungsten.
Carrier Polymer-Agent/Agent Salt Combinations With Excipients and
Other Additives
[0218] The blend of carrier polymer-agent or carrier polymer-agent
salt can comprise various excipients and other additives. The
following Table CPE-1 lists combinations of excipients and other
additives that can be used in combination with agent or salt
thereof and carrier polymer in the compositions making up the
elongate members or segments of elongate members of the gastric
residence systems. These excipients and other additives can be
combined with agent or salt thereof (where the agent or agent salt
comprises between about 10% to about 60% by weight of the
composition) with the carrier polymer, such as polycaprolactone,
making up the remainder of the composition. Excipients include the
following, which can be used individually or in any combination, in
amounts ranging from about 1% to about 30%, such as about 5% to
about 20%, by weight of the composition: Kolliphor P407 (poloxamer
407, poly(ethylene glycol)-block-poly(propylene
glycol)-block-poly(ethylene glycol)), Eudragit RS (Poly[Ethyl
acrylate, methyl methacrylate, trimethylammonioethyl methacrylate
chloride] 1:2:0.1), Eudragit RL (Poly[Ethyl acrylate, methyl
methacrylate, trimethylammonioethyl methacrylate chloride]
1:2:0.2), PDO (polydioxanone), PEG-PCL, SIF (FaSSIF/FaSSGF powder
from BioRelevant), EPO (dimethylaminoethyl methacrylate--butyl
methacrylate--methyl methacrylate copolymer), Kollidon VA64
(vinylpyrrolidone--vinyl acetate copolymer in a ratio of 6:4 by
mass), polyvinyl acetate, polyvinyl pyrrolidine.
[0219] Other additives include silicon dioxide (comprising, for
example, about 0.1% to about 5% by weight of the composition, such
as about 0.1% to 1% or about 0.5%) and an anti-oxidant, such as
alpha-tocopherol (comprising, for example, about 0.1% to about 5%
by weight of the composition, such as about 0.1% to 1% or about
0.5%). Each row of the table below represents a formulation of
excipients and other additives for use with the carrier polymer and
agent or salt thereof.
TABLE-US-00004 TABLE CPE-1 Excipients and additives, in combination
with agent or salt thereof and carrier polymer EPO, P407, Silica,
.alpha.-tocopherol EPO, Silica, .alpha.-tocopherol Eudragit RL,
Eudragit RS, Kolliphor P407, Silica, .alpha.-tocopherol Eudragit
RL, Kolliphor P407, Silica, .alpha.-tocopherol Eudragit RL,
Eudragit RS, Kolliphor P407, Silica, .alpha.-tocopherol Eudragit
RL, Kolliphor P407, Silica, .alpha.-tocopherol Eudragit RL,
Kolliphor P407, Silica, .alpha.-tocopherol Eudragit RS, P407,
Silica, .alpha.-tocopherol Eudragit RS, Silica, .alpha.-tocopherol
Kollidon VA64, Silica, .alpha.-tocopherol Kolliphor P407, Silica,
.alpha.-tocopherol Kolliphor RH40, Silica, .alpha.-tocopherol PDO,
Silica, .alpha.-tocopherol PEG-PCL, Silica, .alpha.-tocopherol Poly
Vinyl Acetate, Silica, .alpha.-tocopherol PVP, Silica,
.alpha.-tocopherol SIF, Silica, .alpha.-tocopherol Silica, P188,
P407, .alpha.-tocopherol Silica, .alpha.-tocopherol
[0220] Table CPE-2 lists specific amounts of excipients and other
additives that can be used in combination with agent or salt
thereof and carrier polymer in the compositions making up the
elongate members or segments of elongate members of the gastric
residence systems.
[0221] The amounts listed in Table CPE-2 can be varied by
plus-or-minus 20% of each ingredient (for example, 0.5% silica can
vary between 0.4% and 0.6% silica, as 20% of 0.5% is 0.1%). Each
row of the table below represents a formulation of excipients and
other additives for use with the carrier polymer and agent or salt
thereof.
TABLE-US-00005 TABLE CPE-2 Excipients and additives, in combination
with agent or salt thereof and carrier polymer 0.5% Silica, 0.5%
.alpha.-tocopherol 0.5% Silica, 2% P407, 0.5% .alpha.-tocopherol
0.5% Silica, 2% P188, 2% P407, 0.5% .alpha.-tocopherol 0.5% Silica,
3% Eudragit RS, 2% P407, 0.5% .alpha.-tocopherol 1% Kolliphor P407,
0.5% Silica, 0.5% .alpha.-tocopherol 10% Eudragit RS, 2.5% P407, 2%
Silica, 0.5% .alpha.-tocopherol 10% Eudragit RS, 5% P407, 0.5%
Silica, 0.5% .alpha.-tocopherol 10% Eudragit RS, 5% P407, 2%
Silica, 0.5% .alpha.-tocopherol 12% Eudragit RL, 3% Kolliphor P407,
0.5% Silica, 0.5% .alpha.-tocopherol 12% Eudragit RL, 5% Kolliphor
P407, 0.5% Silica, 0.5% .alpha.-tocopherol 14.78% Eudragit RS,
0.226% P407, 0.5% Silica, 0.5% .alpha.-tocopherol 17.5% Eudragit
RS, 5% P407, 0.5% Silica, 0.5% .alpha.-tocopherol 19.8% Eudragit
RS, 0.5% Silica, 0.5% .alpha.-tocopherol 2% Kolliphor P407, 0.5%
Silica, 0.5% .alpha.-tocopherol 2% P407, 0.5% Silica, 0.5%
.alpha.-tocopherol 20% Eudragit RS, 2% P407, 0.5% Silica, 0.5%
.alpha.-tocopherol 21.25% Eudragit RS, 2.5% P407, 0.5% Silica, 0.5%
.alpha.-tocopherol 25% Eudragit RL, 5% P407, 0.5% Silica, 0.5%
.alpha.-tocopherol 25% Eudragit RS, 0.5% Silica, 0.5%
.alpha.-tocopherol 25% Eudragit RS, 5% P407, 0.5% Silica, 0.5%
.alpha.-tocopherol 3% Eudragit RL, 9% Eudragit RS, 5% Kolliphor
P407, 0.5% Silica, 0.5% .alpha.-tocopherol 3.5% Eudragit RS, 2.5%
P407, 2% Silica, 0.5% .alpha.-tocopherol 3.5% Eudragit RS, 5% P407,
2% Silica, 0.5% .alpha.-tocopherol 30% PDO, 0.5% Silica, 0.5%
.alpha.-tocopherol 39.5% PEG-PCL, 0.36% Silica, 0.36%
.alpha.-tocopherol 4.5% EPO, 4.5% P407, 0.5% Silica, 0.5%
.alpha.-tocopherol 5% Kolliphor P407, 0.5% Silica, 0.5%
.alpha.-tocopherol 5% Kolliphor RH40, 0.5% Silica, 0.5%
.alpha.-tocopherol 5% SIF, 0.5% Silica, 0.5% .alpha.-tocopherol 6%
Eudragit RL, 5% Kolliphor P407, 0.5% Silica, 0.5%
.alpha.-tocopherol 6% Eudragit RL, 6% Eudragit RS, 5% Kolliphor
P407, 0.5% Silica, 0.5% .alpha.-tocopherol 6.75% Eudragit RS, 3.75%
P407, 2% Silica, 0.5% .alpha.-tocopherol 7% EPO, 2% P407, 0.5%
Silica, 0.5% .alpha.-tocopherol 9% EPO, 0.5% Silica, 0.5%
.alpha.-tocopherol 9% Eudragit RL, 3% Eudragit RS, 5% Kolliphor
P407, 0.5% Silica, 0.5% .alpha.-tocopherol 9% Kollidon VA64, 0.5%
Silica, 0.5% .alpha.-tocopherol 9% Poly Vinyl Acetate, 0.5% Silica,
0.5% .alpha.-tocopherol 9% PVP, 0.5% Silica, 0.5%
.alpha.-tocopherol 9% SIF, 0.5% Silica, 0.5% .alpha.-tocopherol
Manufacture/Assembly of System: Three-Dimensional Printing
[0222] Three-dimensional printing of components of the gastric
residence system, such as arm or arm segments, is performed using
commercially-available equipment. Three-dimensional printing has
been used for pharmaceutical preparation; see Khaled et al.,
"Desktop 3D printing of controlled release pharmaceutical bilayer
tablets," International Journal of Pharmaceutics 461:105-111
(2014); U.S. Pat. No. 7,276,252; Alhnan et al., "Emergence of 3D
Printed Dosage Forms: Opportunities and Challenges," Pharm. Res.,
May 18, 2016, PubMed PMID: 27194002); Yu et al., "Three-dimensional
printing in pharmaceutics: promises and problems," J. Pharm. Sci.
97(9):3666-3690 (2008); and Ursan et al., "Three-dimensional drug
printing: A structured review," J. Am. Pharm. Assoc. 53(2):136-44
(2013).
[0223] The initial feedstocks for three-dimensional printing are
polymers or polymer blends (e.g. enteric polymers, time-dependent
polymers, or blends of one or more of an agent, an agent salt, a
drug, an excipient, etc., with a carrier polymer, enteric polymers,
or time-dependent polymers). The polymer or ingredients which are
to be used for one region of the segment or elongate member to be
manufactured are mixed and pelletized using hot melt extrusion. The
polymer or blended polymer material is extruded through a circular
die, creating a cylindrical fiber which is wound around a
spool.
[0224] Multiple spools are fed into the 3D printer (such as a Hyrel
Printer, available from Hyrel 3D, Norcross, Ga., United States), to
be fed into their representative print heads. The print heads heat
up and melt the material at the nozzle, and lay down a thin layer
of material (polymer or polymer blend) in a specific position on
the piece being manufactured. The material cools and hardens within
seconds, and the next layer is added until the complete structure
is formed. The quality of the dosage form is dependent on the feed
rate, nozzle temperature, and printer resolution; feed rate and
nozzle temperature can be adjusted to obtain the desired
quality.
[0225] Three-dimensional printing can be used to manufacture
individual elongate members, or segments of elongate members.
Three-dimensional printing can also be used to prepare a bulk
configuration, such as a consolidated "slab," similar to that
prepared by co-extrusion methods described herein. The bulk
configuration can be cut into individual pieces (that is,
individual elongate members or individual segments) as needed.
[0226] In some embodiments of the invention, producing an entire
elongate member, or "arm," of the gastric residence system by
three-dimensional printing of the elongate member is contemplated.
In some embodiments of the invention, producing a segment of an
elongate member, or "arm," of the gastric residence system by
three-dimensional printing of the segment of an elongate member is
contemplated. In some embodiments, an elongate member or a segment
thereof is produced by three-dimensional printing of adjacent
portions of carrier polymer-agent or polymer-agent salt blend and
linker material in a bulk configuration, such as a slab
configuration. The three-dimensional printing can be followed by
cutting the bulk configuration into pieces which have the desired
shape of the elongate member or segment thereof. The
three-dimensional printing can be followed by compression molding
of portions of the bulk configuration into pieces which have the
desired shape of the elongate member or segment thereof.
[0227] Three-dimensional printing is often accomplished by feeding
a rod or fiber of a solid material to a print head, where it is
melted and deposited with subsequent solidification, in a technique
known as fused deposition modeling (sometimes also called extrusion
deposition); see U.S. Pat. Nos. 5,121,329 and 5,340433. The methods
described herein for the manufacture of carrier polymer-drug
components can also be used to manufacture feed material, which can
be used in the manufacture via three-dimensional printing of
components of the gastric residence systems.
Manufacture/Assembly of System: Co-Extrusion
[0228] Components of the gastric residence systems can be
manufactured by co-extrusion. Most of the various configurations
for the segments discussed herein, such as the "islands-in-the-sea"
configurations, can be made by either three-dimensional printing or
co-extrusion. However, co-extrusion is less expensive, and can be
run as a continuous process, as opposed to three-dimensional
printing, which is generally run as a batch process.
[0229] Co-extrusion of the "islands-in-the-sea" configuration is
used in the textile industry and for production of fiber optics,
but has rarely been applied in biomedical systems. See U.S. Pat.
Nos. 3,531,368; 3,716,614; 4,812,012; and Haslauer et al., J.
Biomed. Mater. Res. B Appl. Biomater. 103(5):1050-8 (2015)).
[0230] Co-extrusion of components of the gastric residence system,
such as an elongate member (arm), or a segment of an elongate
member (arm), can be performed using commercially-available
equipment, combined with customized co-extruder plumbing and
customized dies for the desired configuration. The initial
feedstocks for co-extrusion are polymers or polymer blends (e.g.
enteric polymers, time-dependent polymers, or blends of one or more
of an agent, an agent salt, a drug, an excipient, etc., with a
carrier polymer, enteric polymers, or time-dependent polymers). The
polymer or ingredients which are to be used for one region of the
segment or elongate member to be manufactured are mixed and
pelletized using hot melt extrusion. The polymer pellets thus
formed are placed into hoppers above single screw extruders and
dried to remove surface moisture. Pellets are gravimetrically fed
into individual single-screw extruders, where they are melted and
pressurized for co-extrusion.
[0231] The appropriate molten polymers are then pumped through
custom designed dies with multiple channels where they form the
required geometry. The composite polymer block is cooled
(water-cooled, air-cooled, or both) and cut or stamped into the
desired shape, including, but not limited to, such shapes as
triangular prisms, rectangular prisms, or cylinder sections
(pie-shaped wedges).
[0232] In some embodiments of the invention, producing an entire
elongate member, or "arm," of the gastric residence system by
co-extruding the elongate member is contemplated. In some
embodiments of the invention, producing a segment of an elongate
member, or "arm," of the gastric residence system by co-extruding
the segment of an elongate member is contemplated. In some
embodiments, an elongate member or a segment thereof is produced by
co-extruding adjacent portions of carrier polymer-agent or carrier
polymer-agent salt blend and linker material in a bulk
configuration, such as a slab configuration. The co-extruding can
be followed by cutting the bulk configuration into pieces which
have the desired shape of the elongate member or segment thereof.
The co-extruding can be followed by compression molding of portions
of the bulk configuration into pieces which have the desired shape
of the elongate member or segment thereof.
[0233] In some embodiments, an elongate member or a segment thereof
is produced by co-extruding adjacent portions of carrier
polymer-agent or carrier polymer-agent salt blend and linker
material in a bulk configuration, such as a slab configuration,
while also co-extruding an additional polymer or polymers within
the carrier polymer-agent or carrier polymer-agent salt blend, the
linker material, or both the carrier polymer-agent (or agent salt)
blend and the linker material. The co-extruding the additional
polymer or polymers within the carrier polymer-agent or carrier
polymer-agent salt blend, the linker material, or both the carrier
polymer-agent (or agent salt) blend and the linker material can be
performed in an islands-in-the-sea configuration. The co-extruding
can be followed by cutting the bulk configuration into pieces which
have the desired shape of the elongate member or segment thereof.
The co-extruding can be followed by compression molding of portions
of the bulk configuration into pieces which have the desired shape
of the elongate member or segment thereof.
Agent Particle Size and Milling
[0234] Control of particle size used in the gastric residence
systems is important for both optimal release of agent and
mechanical stability of the systems. The particle size of the
agents affects the surface area of the agents available for
dissolution when gastric fluid permeates the carrier polymer-agent
segments of the system. Also, as the "arms" (elongate members) of
the systems are relatively thin in diameter (for example, 1
millimeter to 5 millimeters), the presence of a particle of agent
of a size in excess of a few percent of the diameter of the arms
will result in a weaker arm, both before the agent elutes from the
device, and after elution when a void is left in the space formerly
occupied by the agent particle. Such weakening of the arms is
disadvantageous, as it may lead to premature breakage and passage
of the system before the end of the desired residence period.
[0235] In one embodiment, the agent particles used for blending
into the carrier polymer-agent components are smaller than about
100 microns in diameter. In another embodiment, the agent particles
are smaller than about 75 microns in diameter. In another
embodiment, the agent particles are smaller than about 50 microns
in diameter. In another embodiment, the agent particles are smaller
than about 40 microns in diameter. In another embodiment, the agent
particles are smaller than about 30 microns in diameter. In another
embodiment, the agent particles are smaller than about 25 microns
in diameter. In another embodiment, the agent particles are smaller
than about 20 microns in diameter. In another embodiment, the agent
particles are smaller than about 10 microns in diameter. In another
embodiment, the agent particles are smaller than about 5 microns in
diameter.
[0236] In one embodiment, at least about 80% of the agent particles
used for blending into the carrier polymer-agent components are
smaller than about 100 microns in diameter. In another embodiment,
at least about 80% of the agent particles are smaller than about 75
microns in diameter. In another embodiment, at least about 80% of
the agent particles are smaller than about 50 microns in diameter.
In another embodiment, at least about 80% of the agent particles
are smaller than about 40 microns in diameter. In another
embodiment, at least about 80% of the agent particles are smaller
than about 30 microns in diameter. In another embodiment, at least
about 80% of the agent particles are smaller than about 25 microns
in diameter. In another embodiment, at least about 80% of the agent
particles are smaller than about 20 microns in diameter. In another
embodiment, at least about 80% of the agent particles are smaller
than about 10 microns in diameter. In another embodiment, at least
about 80% of the agent particles are smaller than about 5 microns
in diameter.
[0237] In one embodiment, at least about 80% of the mass of the
agent particles used for blending into the carrier polymer-agent
components have sizes between about 1 micron and about 100 microns
in diameter. In another embodiment, at least about 80% of the mass
of the agent particles have sizes between about 1 micron and about
75 microns in diameter. In another embodiment, at least about 80%
of the mass of the agent particles have sizes between about 1
micron and about 50 microns in diameter. In another embodiment, at
least about 80% of the mass of the agent particles have sizes
between about 1 micron and about 40 microns in diameter. In another
embodiment, at least about 80% of the mass of the agent particles
have sizes between about 1 micron and about 30 microns in diameter.
In another embodiment, at least about 80% of the mass of the agent
particles have sizes between about 1 micron and about 25 microns in
diameter. In another embodiment, at least about 80% of the mass of
the agent particles have sizes between about 1 micron and about 20
microns in diameter. In another embodiment, at least about 80% of
the mass of the agent particles have sizes between about 1 micron
and about 10 microns in diameter. In another embodiment, at least
about 80% of the mass of the agent particles have sizes between
about 1 micron and about 5 microns in diameter.
[0238] In one embodiment, at least about 80% of the mass of the
agent particles used for blending into the carrier polymer-agent
components have sizes between about 2 microns and about 100 microns
in diameter. In another embodiment, at least about 80% of the mass
of the agent particles have sizes between about 2 microns and about
75 microns in diameter. In another embodiment, at least about 80%
of the mass of the agent particles have sizes between about 2
microns and about 50 microns in diameter. In another embodiment, at
least about 80% of the mass of the agent particles have sizes
between about 2 microns and about 40 microns in diameter. In
another embodiment, at least about 80% of the mass of the agent
particles have sizes between about 2 microns and about 30 microns
in diameter. In another embodiment, at least about 80% of the mass
of the agent particles have sizes between about 2 microns and about
25 microns in diameter. In another embodiment, at least about 80%
of the mass of the agent particles have sizes between about 2
microns and about 20 microns in diameter. In another embodiment, at
least about 80% of the mass of the agent particles have sizes
between about 2 microns and about 10 microns in diameter. In
another embodiment, at least about 80% of the mass of the agent
particles have sizes between about 2 microns and about 5 microns in
diameter.
[0239] In one embodiment, at least about 80% of the mass of the
agent particles used for blending into the carrier polymer-agent
components have sizes between about 5 microns and about 100 microns
in diameter. In another embodiment, at least about 80% of the mass
of the agent particles have sizes between about 5 microns and about
75 microns in diameter. In another embodiment, at least about 80%
of the mass of the agent particles have sizes between about 5
microns and about 50 microns in diameter. In another embodiment, at
least about 80% of the mass of the agent particles have sizes
between about 5 microns and about 40 microns in diameter. In
another embodiment, at least about 80% of the mass of the agent
particles have sizes between about 5 microns and about 30 microns
in diameter. In another embodiment, at least about 80% of the mass
of the agent particles have sizes between about 5 microns and about
25 microns in diameter. In another embodiment, at least about 80%
of the mass of the agent particles have sizes between about 5
microns and about 20 microns in diameter. In another embodiment, at
least about 80% of the mass of the agent particles have sizes
between about 5 microns and about 10 microns in diameter.
[0240] The particle size of the agents can be readily adjusted by
milling. Several milling techniques are available to reduce larger
particles to smaller particles of desired size. Fluid energy
milling is a dry milling technique which uses inter-particle
collisions to reduce the size of particles. A type of fluid energy
mill called an air jet mill shoots air into a cylindrical chamber
in a manner so as to maximize collision between agent particles.
Ball milling utilizes a rolling cylindrical chamber which rotates
around its principal axis. The agent and grinding material (such as
steel balls, made from chrome steel or CR-NI steel; ceramic balls,
such as zirconia; or plastic polyamides) collide, causing reduction
in particle size of the agent. Ball milling can be performed in
either the dry state, or with liquid added to the cylinder where
the agent and the grinding material are insoluble in the liquid.
Further information regarding milling is described in the chapter
by R. W. Lee et al. entitled "Particle Size Reduction" in
Water-Insoluble Drug Formulation, Second Edition (Ron Liu, editor),
Boca Raton, Fla.: CRC Press, 2008; and in the chapter by A. W.
Brzeczko et al. entitled "Granulation of Poorly Water-Soluble
Drugs" in Handbook of Pharmaceutical Granulation Technology, Third
Edition (Dilip M. Parikh, editor), Boca Raton, Fla.: CRC
Press/Taylor & Francis Group, 2010 (and other sections of that
handbook). Fluid energy milling (i.e., air jet milling) is a
preferred method of milling, as it is more amenable to scale-up
compared to other dry milling techniques such as ball milling.
Willing Additives
[0241] Substances can be added to the agent material during milling
to assist in obtaining particles of the desired size, and minimize
aggregation during handling. Silica (silicon dioxide, SiO.sub.2) is
a preferred milling additive, as it is inexpensive, widely
available, and non-toxic. Other additives which can be used include
silica, calcium phosphate, powdered cellulose, colloidal silicon
dioxide, hydrophobic colloidal silica, magnesium oxide, magnesium
silicate, magnesium trisilicate, talc, polyvinylpyrrolidone,
cellulose ethers, polyethylene glycol, polyvinyl alcohol, and
surfactants. In particular, hydrophobic particles less than 5
microns in diameter are particularly prone to agglomeration, and
hydrophilic additives are used when milling such particles. A
weight/weight ratio of about 0.1% to about 5% of milling additive,
such as silica, can be used for fluid milling or ball milling, or
about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about
2%, about 0.1% to about 1%, about 1% to about 5%, about 1% to about
4%, about 1% to about 3%, about 1% to about 2 or about 0.1%, about
0.5%, about 1%, about 2%, about 3%, about 4% or about 5%.
Particle Sizing
[0242] After milling, particles can be passed through meshes of
appropriate size to obtain particles of the desired size. To obtain
particles of a desired maximum size, particles are passed through a
mesh with holes of the maximum size desired; particles which are
too large will be retained on the mesh, and particles which pass
through the mesh will have the desired maximum size. To obtain
particles of a desired minimum size, particles are passed through a
mesh with holes of the minimum size desired; particles which pass
through the mesh are too small, and the desired particles will be
retained on the mesh.
Coupling Polymers
[0243] The coupling polymer is used to link one or more carrier
polymer-agent components to one or more carrier polymer-agent
components, to link one or more carrier polymer-agent components to
one or more elastomer components, or to link one or more elastomer
components to one or more elastomer components. Thus, the coupling
polymers form linker regions between other components of the
system. Enteric polymers and time-dependent polymers are preferred
for use as coupling polymers. In some embodiments, enteric polymers
are used as coupling polymers. In some embodiments, time-dependent
polymers which are pH-resistant, that is, less sensitive to changes
in pH than enteric polymers, are used as coupling polymers. In some
embodiments, both enteric polymers and time-dependent polymers
which are less sensitive to changes in pH than enteric polymers are
used as coupling polymers.
[0244] Enteric polymers are relatively insoluble under acidic
conditions, such as the conditions encountered in the stomach, but
are soluble under the less acidic to basic conditions encountered
in the small intestine. Enteric polymers which dissolve at about pH
5 or above can be used as coupling polymers, as the pH of the
initial portion of the small intestine, the duodenum, ranges from
about 5.4 to 6.1. If the gastric residence system passes intact
through the pyloric valve, the enteric coupling polymer will
dissolve and the components linked by the coupling polymer will
break apart, allowing passage of the residence system through the
small and large intestines. Thus, the gastric residence systems are
designed to uncouple rapidly in the intestinal environment by
dissolution of the coupling polymer, within 48 hours, preferably
within 24 hours, more preferably within 12 hours, yet more
preferably within 1-2 hours, so as to avoid potential intestinal
blockage. If, during treatment, the gastric residence system must
be removed quickly for any reason, the patient can drink a mildly
basic aqueous solution (such as a bicarbonate solution) in order to
induce immediate de-coupling of the gastric residence system.
[0245] By "time-dependent polymer which are pH-resistant" (or
equivalently, "pH-resistant time-dependent polymers") is meant
that, under conditions where an enteric polymer would degrade to
the point that it would no longer link the components together, the
time-dependent polymer will still have sufficient mechanical
strength to link the components together. In sonic embodiments, the
time-dependent polymer retains about the same linking capacity,
that is, about 100% of its linkage strength, after exposure to a
solution between about pH 7 to about pH 8 as it has after exposure
to a solution between about pH 2 to about pH 3, where the exposure
is for about an hour, about a day, about three days, or about a
week. In sonic embodiments, the time-dependent polymer retains at
least about 90% of its linkage strength, after exposure to a
solution between about pH 7 to about pH 8 as it has after exposure
to a solution between about pH 2 to about pH 3, where the exposure
is for about an hour, about a day, about three days, or about a
week. In some embodiments, the time-dependent polymer retains at
least about 75% of its linkage strength, after exposure to a
solution between about pH 7 to about pH 8 as it has after exposure
to a solution between about pH 2 to about pH 3, where the exposure
is for about an hour, about a day, about three days, or about a
week. In sonic embodiments, the time-dependent polymer retains at
least about 60% of its linkage strength, after exposure to a
solution between about pH 7 to about pH 8 as it has after exposure
to a solution between about pH 2 to about pH 3, where the exposure
is for about an hour, about a day, about three days, or about a
week. In some embodiments, the time-dependent polymer retains at
least about 50% of its linkage strength, after exposure to a
solution between about pH 7 to about pH 8 as it has after exposure
to a solution between about pH 2 to about pH 3, where the exposure
is for about an hour, about a day, about three days, or about a
week. In some embodiments, the time-dependent polymer retains at
least about 25% of its linkage strength, after exposure to a
solution between about pH 7 to about pH 8 as it has after exposure
to a solution between about pH 2 to about pH 3, where the exposure
is for about an hour, about a day, about three days, or about a
week. In some embodiments, the time-dependent polymer resists
breaking under a flexural force of about 0.2 Newtons (N), about 0.3
N, about 0.4 N, about 0.5 N, about 0.75 N, about 1 N, about 1.5 N,
about 2 N, about 2.5 N, about 3 N, about 4 N, or about 5 N, after
exposure to a solution between about pH 7 to about pH 8, where the
exposure is for about an hour, about a day, about three days, or
about a week. Linkage strength can be measured by any relevant test
that serves to test coupling ability, such as a four-point bending
flexural test (ASTM D790).
[0246] Exemplary coupling polymers include, but are not limited to,
cellulose acetate phthalate, cellulose acetate succinate,
methylcellulose phthalate, ethylhydroxycellulose phthalate,
polyvinylacetatephthalate, polyvinylbutyrate acetate, vinyl
acetate-maleic anhydride copolymer, styrene-maleic mono-ester
copolymer, methacrylic acid methylmethacrylate copolymer, methyl
acrylate-methacrylic acid copolymer, methacrylate-methacrylic
acid-octyl acrylate copolymer, and copolymers, mixtures, blends and
combinations thereof. Some of the enteric polymers that can be used
in the invention are listed in the Enteric Polymer Table, along
with their dissolution pH. (See Mukherji, Gour and Clive G. Wilson,
"Enteric Coating for Colonic Delivery," Chapter 18 of
Modified-Release Drug Delivery Technology (editors Michael J.
Rathbone, Jonathan Hadgraft, Michael S. Roberts), Drugs and the
Pharmaceutical Sciences Volume 126, New York: Marcel Dekker, 2002.)
Preferably, enteric polymers that dissolve at a pH of no greater
than about 5 or about 5.5 are used. Poly(methacrylic acid-co-ethyl
acrylate) (sold under the trade name EUDRAGIT L 100-55; EUDRAGIT is
a registered trademark of Evonik Rohm GmbH, Darmstadt, Germany) is
a preferred enteric polymer. Another preferred enteric polymer is
hydroxypropylmethylcellulose acetate succinate (hypromellose
acetate succinate or HPMCAS; Ashland, Inc., Covington, Ky., USA),
which has a tunable pH cutoff from about 5.5 to about 7.0.
Cellulose acetate phthalate, cellulose acetate succinate, and
hydroxypropyl methylcellulose, phthalate are also suitable enteric
polymers.
[0247] In one embodiment, the enteric polymers used in the gastric
residence system dissolve at a pH above about 4. In some
embodiments, the enteric polymers used in the gastric residence
system dissolve at a pH above about 5. In some embodiments, the
enteric polymers used in the gastric residence system dissolve at a
pH above about 6. In some embodiments, the enteric polymers used in
the gastric residence system dissolve at a pH above about 7. In
some embodiments, the enteric polymers used in the gastric
residence system dissolve at a pH above about 7.5. In some
embodiments, the enteric polymers used in the gastric residence
system dissolve at a pH between about 4 and about 5. In some
embodiments, the enteric polymers used in the gastric residence
system dissolve at a pH between about 4 and about 6. In some
embodiments, the enteric polymers used in the gastric residence
system dissolve at a pH between about 4 and about 7. In some
embodiments, the enteric polymers used in the gastric residence
system dissolve at a pH between about 4 and about 7.5. In some
embodiments, the enteric polymers used in the gastric residence
system dissolve at a pH between about 5 and about 6. In some
embodiments, the enteric polymers used in the gastric residence
system dissolve at a pH between about 5 and about 7. In some
embodiments, the enteric polymers used in the gastric residence
system dissolve at a pH between about 5 and about 7.5. In some
embodiments, the enteric polymers used in the gastric residence
system dissolve at a pH between about 6 and about 7. In some
embodiments, the enteric polymers used in the gastric residence
system dissolve at a pH between about 6 and about 7.5.
TABLE-US-00006 Enteric Polymer Table Dissolution Polymer pH
Cellulose acetate phthalate 6.0-6.4 Hydroxypropyl 4.8
methylcellulose phthalate 50 Hydroxypropyl 5.2 methylcellulose
phthalate 55 Polyvinylacetate phthalate 5.0 Methacrylic acid-methyl
6.0 methacrylate copolymer (1:1) Methacrylic acid-methyl 6.5-7.5
methacrylate copolymer (2:1) Methacrylic acid-ethyl 5.5 acrylate
copolymer (2:1) Shellac 7.0 Hydroxypropyl 7.0 methylcellulose
acetate succinate Poly (methyl vinyl 4.5-5.0 ether/maleic acid)
monoethyl ester Poly (methyl vinyl 5.4 ether/maleic acid) n-butyl
ester
[0248] Additional preferred polymers for use as coupling polymers
are time-dependent polymers, that is, polymers that degrade in a
time-dependent manner in the gastric environment. For example, the
liquid plasticizer triacetin releases from a polymer formulation in
a time-dependent manner over seven days in simulated gastric fluid,
while Plastoid B retains its strength over a seven-day period in
simulated gastric fluid. Thus, a polymer that degrades in a
time-dependent manner can be readily prepared by mixing Plastoid B
and triacetin; the degradation time of the Plastoid B-triacetin
mixture can be extended by increasing the amount of Plastoid B used
in the mixture (that is, using less triacetin in the mixture),
while the degradation time can be decreased by decreasing the
amount of Plastoid B used in the mixture (that is, using more
triacetin in the mixture).
[0249] A variety of time-dependent mechanisms are available.
Water-soluble time-dependent polymers break down as water
penetrates through the polymer. Examples of such polymers are
hydroxypropyl methylcellulose and poly vinyl acetate. Acid soluble
time-dependent polymers break down over time in an acidic
environment. Examples include Eudragit EPO. Time-dependent polymers
can use water soluble plasticizers; as plasticizer is released, the
remaining polymer becomes brittle and breaks under gastric forces.
Examples of such polymers include triacetin and triethyl
citrate.
[0250] In some embodiments, the carrier polymer-agent components
are elongate members comprised of segments attached by enteric
polymers. In some embodiments, the carrier polymer-agent components
are attached to the elastomer component of the system by enteric
polymers. In any of these embodiments, when enteric polymers are
used for both segment-to-segment attachments and for attachment of
the elongate members to the elastomeric component, the enteric
polymer used for segment-segment attachments can be the same
enteric polymer as the enteric polymer used for attachment of the
elongate members to the elastomeric component, or the enteric
polymer used for segment-segment attachments can be a different
enteric polymer than the enteric polymer used for attachment of the
elongate members to the elastomeric component. The enteric polymers
used for the segment-segment attachments can all be the same
enteric polymer, or can all be different enteric polymers, or some
enteric polymers in the segment-segment attachments can be the same
and some enteric polymers in the segment-segment attachments can be
different. That is, the enteric polymer(s) used for each
segment-segment attachment and the enteric polymer used for
attachment of the elongate members to the elastomeric component can
be independently chosen.
[0251] In sonic embodiments, the carrier polymer-drug components
are non-segmented elongate members attached to the elastomer
component of the system by enteric polymers, time-dependent
linkers, or disintegrating matrices, or by any combination of
enteric polymers, time-dependent linkers, and/or disintegrating
matrices.
[0252] In any of the embodiments of the gastric residence systems
described herein, the coupling polymers or linkers can comprise
hydroxypropyl methyl cellulose acetate succinate (HPMCAS) and
polycaprolactone (PCL). These blends can be used to form
disintegrating linkers or disintegrating matrices. The ratio of
HPMCAS to polycaprolactone in the disintegrating linker or
disintegrating matrix can be between about 80% HPMCAS:20% PCL to
about 20% HPMCAS:80% PCL. the ratio of HPMCAS to polycaprolactone
can be between about 80% HPMCAS:20% PCL to about 20% PMCAS:80% PCL;
between about 70% HPMCAS:30% PCL to about 30% HPMCAS:70% PCL;
between about 60% HPMCAS:40% PCL to about 40% HPMCAS:60% PCL;
between about 80% HPMCAS:20% PCL to about 50% HPMCAS:50% PCL;
between about 80% HPMCAS:20% PCL to about 60% HPMCAS:40% PCL;
between about 70% HPMCAS:30% PCL to about 50% HPMCAS:50% PCL;
between about 70% HPMCAS:30% PCL to about 60% HPMCAS:40% PCL;
between about 20% HPMCAS:80% PCL to about 40% HPMCAS:60% PCL;
between about 20% HPMCAS:80% PCL to about 50% HPMCAS:50% PCL;
between about 30% HPMCAS:70% PCL to about 40% HPMCAS:60% PCL;
between about 30% HPMCAS:70% PCL to about 50% HPMCAS:50% PCL; or
about 80% HPMCAS:20% PCL, about 70% HPMCAS:30% PCL, about 60%
HPMCAS:40% PCL, about 50% HPMCAS:50% PCL, about 40% HPMCAS:60% PCL,
about 30% HPMCAS:70% PCL, or about 20% HPMCAS:80% PCL. The linker
can further comprise a plasticizer selected from the group
consisting of triacetin, triethyl citrate, tributyl citrate,
poloxamers, polyethylene glycol, polypropylene glycol, diethyl
phthalate, dibutyl sebacate, glycerin, castor oil, acetyl triethyl
citrate, acetyl tributyl citrate, polyethylene glycol monomethyl
ether, sorbitol, sorbitan, a sorbitol-sorbitan mixture, and
diacetylated monoglycerides.
[0253] The linkers are chosen to weaken sufficiently after a
specified period of time in order to allow the gastric residence
systems to reach a point where they de-couple and pass through the
pylorus and out of the stomach after the desired residence period
or weaken sufficiently such that the gastric residence system is no
longer retained in the stomach; that is, the linkers weaken to the
point of uncoupling (the uncoupling point) or to the point where
the gastric residence system can pass through the pylorus (the
pyloric passage point, or passage point). Thus, in one embodiment,
linkers are used that uncouple after about two days in a human
stomach; after about three days in a human stomach; after about
four days in a human stomach; after about five days in a human
stomach; after about six days in a human stomach; after about seven
days in a human stomach; after about eight days in a human stomach;
after about nine days in a human stomach; after about ten days in a
human stomach; or after about two weeks in a human stomach. In one
embodiment, linkers are used that uncouple after about two days in
a dog stomach; after about three days in a dog stomach; after about
four days in a dog stomach; after about five days in a dog stomach;
after about six days in a dog stomach; after about seven days in a
dog stomach; after about eight days in a dog stomach; after about
nine days in a dog stomach; after about ten days in a dog stomach;
or after about two weeks in a dog stomach. In one embodiment,
linkers are used that uncouple after about two days in a pig
stomach; after about three days in a pig stomach; after about four
days in a pig stomach; after about five days in a pig stomach;
after about six days in a pig stomach; after about seven days in a
pig stomach; after about eight days in a pig stomach; after about
nine days in a pig stomach; after about ten days in a pig stomach;
or after about two weeks in a pig stomach. In one embodiment,
linkers are used that uncouple after about two days in fasted-state
simulated gastric fluid; after about three days in fasted-state
simulated gastric fluid; after about four days in fasted-state
simulated. gastric fluid; after about five days in fasted-state
simulated gastric fluid; after about six days in fasted-state
simulated gastric fluid; after about seven days in fasted-state
simulated gastric fluid; after about eight days in fasted-state
simulated gastric fluid; after about nine days in fasted-state
simulated gastric fluid; after about ten days in fasted-state
simulated gastric fluid; or after about two weeks in fasted-state
simulated gastric fluid. In one embodiment, linkers are used that
uncouple after about two days in fed-state simulated gastric fluid;
after about three days in fed-state simulated gastric fluid; after
about four days in fed-state simulated gastric fluid; after about
five days in fed-state simulated gastric fluid; after about six
days in fed-state simulated gastric fluid; after about seven days
in fed-state simulated gastric fluid; after about eight days in
fed-state simulated gastric fluid; after about nine days in
fed-state simulated gastric fluid; after about ten days in
fed-state simulated gastric fluid; or after about two weeks in
fed-state simulated gastric fluid. In one embodiment, linkers are
used that uncouple after about two days in water at pH 2; after
about three days in water at pH 2; after about four days in water
at pH 2; after about five days in water at pH 2; after about six
days in water at pH 2; after about seven days in water at pH 2;
after about eight days in water at pH 2; after about nine days in
water at pH 2; after about ten days in water at pH 2; or after
about two weeks in water at pH 2. In one embodiment, linkers are
used that uncouple after about two days in water at pH 1; after
about three days in water at pH 1; after about four days in water
at pH 1; after about five days in water at pH 1; after about six
days in water at pH 1; after about seven days in water at pH 1;
after about eight days in water at pH 1; after about nine days in
water at pH 1; after about ten days in water at pH 1; or after
about two weeks in water at pH 1.
[0254] The de-coupling or pyloric passage point in human, dog, or
pig occurs when the system passes out of the stomach, that is, when
it passes through the pylorus. For the in vitro measurements in
simulated gastric fluid or acidic water, the de-coupling or pyloric
passage point occurs when the linker weakens to the point where it
will break under the normal compressive forces of the stomach,
typically about 0.1 Newton to 0.2 Newton. Linkage strength
(breaking point) can be measured by any relevant test that serves
to test coupling ability, that is, the force required to break the
linker, such as the four-point bending flexural test (ASTM D790)
described in Example 18 of WO 2017/070612, or Examples 12, 13, 15,
17, or 18 of WO 2017/100367. In one embodiment, the de-coupling or
pyloric passage point is reached when the linkers uncouple at about
0.2 N of force. In another embodiment, the de-coupling or pyloric
passage point is reached when the linkers uncouple at about 0.1 N
of force.
[0255] The gastric residence systems can reach the pyloric passage
point without any or all of the linkers actually breaking. If the
linkers weaken or degrade to the point where they can no longer
hold the gastric residence system in the stomach, even if one,
some, or all of the linkers do not break, the gastric residence
system will pass through the pylorus and into the small intestine
(the pyloric passage point or passage point). In some embodiments,
linkers are used that weaken to the passage point after about two
days in a human stomach; after about three days in a human stomach;
after about four days in a human stomach; after about five days in
a human stomach; after about six days in a human stomach; after
about seven days in a human stomach; after about eight days in a
human stomach; after about nine days in a human stomach; after
about ten days in a human stomach: or after about two weeks in a
human stomach. In some embodiments, linkers are used that weaken to
the passage point after about two days in a dog stomach; after
about three days in a dog stomach; after about four days in a dog
stomach; after about five days in a dog stomach; after about six
days in a dog stomach; after about seven days in a dog stomach;
after about eight days in a dog stomach; after about nine days in a
dog stomach; after about ten days in a dog stomach; or after about
two weeks in a dog stomach. In some embodiments, linkers are used
that weaken to the passage point after about two days in a pig
stomach; after about three days in a pig stomach; after about four
days in a pig stomach; after about five days in a pig stomach;
after about six days in a pig stomach; after about seven days in a
pig stomach; after about eight days in a pig stomach; after about
nine days in a pig stomach; after about ten days in a pig stomach;
or after about two weeks in a pig stomach. In some embodiments,
linkers are used that weaken to the passage point after about two
days in fasted-state simulated gastric fluid; after about three
days in fasted-state simulated gastric fluid; after about four days
in fasted-state simulated gastric fluid; after about five days in
fasted-state simulated gastric fluid; after about six days in
fasted-state simulated gastric fluid; after about seven days in
fasted-state simulated gastric fluid; after about eight days in
fasted-state simulated gastric fluid; after about nine days in
fasted-state simulated gastric fluid; after about ten days in
fasted-state simulated gastric fluid; or after about two weeks in
fasted-state simulated gastric fluid. In some embodiments, linkers
are used that weaken to the passage point after about two days in
fed-state simulated gastric fluid; after about three days in
fed-state simulated gastric fluid; after about four days in
fed-state simulated gastric fluid; after about five days in
fed-state simulated gastric fluid; after about six days in
fed-state simulated gastric fluid; after about seven days in
fed-state simulated gastric fluid; after about eight days in
fed-state simulated gastric fluid; after about nine days in
fed-state simulated gastric fluid; after about ten days in
fed-state simulated gastric fluid; or after about two weeks in
fed-state simulated gastric fluid. In some embodiments, linkers are
used that weaken to the passage point after about two days in water
at pH 2; after about three days in water at pH 2; after about four
days in water at pH 2; after about five days in water at pH 2;
after about six days in water at pH 2; after about seven days in
water at pH 2; after about eight days in water at pH 2; after about
nine days in water at pH 2; after about ten days in water at pH 2;
or after about two weeks in water at pH 2. In some embodiments,
linkers are used that weaken to the passage point after about two
days in water at pH 1; after about three days in water at pH 1;
after about four days in water at pH 1; after about five days in
water at pH 1; after about six days in water at pH 1; after about
seven days in water at pH 1; after about eight days in water at pH
1; after about nine days in water at pH 1; after about ten days in
water at pH I; or after about two weeks in water at pH I.
Elastomers
[0256] Elastomers (also referred to as elastic polymers or tensile
polymers) enable the gastric residence system to be compacted, such
as by being folded or compressed, into a form suitable for
administration to the stomach by swallowing a container or capsule
containing the compacted system. Upon dissolution of the capsule in
the stomach, the gastric residence system expands into a shape
which prevents passage of the system through the pyloric sphincter
of the patient for the desired residence time of the system. Thus,
the elastomer must be capable of being stored in a compacted
configuration in a capsule for a reasonable shelf life, and of
expanding to its original shape, or approximately its original
shape, upon release from the capsule. In one embodiment, the
elastomer is a silicone elastomer. In one embodiment, the elastomer
is formed from a liquid silicone rubber (LSR), such as sold in the
Dow Coming QP-1 liquid silicone rubber kit. In one embodiment, the
elastomer is crosslinked polycaprolactone. In one embodiment, the
elastomer is an enteric polymer, such as those listed in the
Enteric Polymer Table. In some embodiments, the coupling polymer(s)
used in the system are also elastomers. Elastomers are preferred
for use as the central polymer in the star-shaped or stellate
design of the gastric residence systems.
[0257] In one embodiment, both the coupling polymer and elastomer
are enteric polymers, which provides for more complete breakage of
the system into the carrier polymer-agent pieces if the system
enters the intestine, or if the patient drinks a mildly basic
solution in order to induce passage of the system.
[0258] Examples of elastomers which can be used include silicones,
such as those formed using Dow Coming QP-1 kits;
urethane-cross-linked polycaprolactones; poly(acryloyl
6-aminocaproic acid) (PA6ACA); poly(methacrylic acid-co-ethyl
acrylate) (EUDRAGIT L, 100-55); and mixtures of poly(acryloyl
6-aminocaproic acid) (PA6ACA) and poly(methacrylic acid-co-ethyl
acrylate) (EUDRAGIT L 100-55).
[0259] Flexible coupling polymers, i.e., elastomeric coupling
polymers or elastomers, are used as the central polymer in the
star-shaped or stellate design of the gastric residence systems. A
particularly preferred elastomer for use as the central elastomer
of the stellate or star configuration is silicone rubber. Liquid
silicone rubber (LSR) can be molded easily and cured into a desired
shape. The Dow Coming QP-1 series, comprising cross-linked dimethyl
and methyl-vinyl siloxane copolymers and reinforcing silica, are
examples of such silicone rubber polymers (see, for example, the
Web site www.dowcoming.com/DataFiles/090276fe8018ed07.pdf.
Non-segmented elongate members or elongate members comprising
segments of carrier polymer-agent components can then be attached
to the central silicone rubber elastomer. Another elastomer which
can be used as the central elastomer in the stellate design is
crosslinked polycaprolactone.
[0260] Specific configurations of gastric residence systems are
disclosed in International Patent Application No. WO 2017/100367,
and any of those configurations can be used for the gastric
residence systems disclosed herein.
System Dimensions
[0261] The system must be able to adopt a compacted state with
dimensions that enable the patient to swallow the system (or for
the system to be introduced into the stomach by alternate means,
such as a feeding tube or gastrostomy tube). Typically, the system
is held in the compacted state by a container such as a capsule.
Upon entry into the stomach, the system is then released from the
container and adopts an uncompacted state, that is, an expanded
conformation, with dimensions that prevent passage of the system
through the pyloric sphincter, thus permitting retention of the
system in the stomach.
[0262] Accordingly, the system should be capable of being placed
inside a standard-sized capsule of the type commonly used in
pharmacy. Standard capsule sizes in use in the United States are
provided below in the Capsule Table below (see "Draft Guidance for
industry on Size, Shape, and Other Physical Attributes of Generic
Tablets and Capsules" at URL
www.regulations.gov/#!documentDetail;D=FDA-2013-N-1434-0002). As
these are the outer dimensions of the capsule, and as dimensions
will vary slightly between capsule manufacturers, the system should
be capable of adopting a configuration which is about 0.5 to 1 mm
smaller than the outer diameter shown, and about 1 to 2 mm shorter
than the length shown in the Capsule Table.
TABLE-US-00007 Capsule Table Outer Capsule Diameter Length Size
(mm) (mm) 000 9.9 26.1 00 8.5 23.3 0 7.6 21.7 1 6.9 19.4 2 6.3 18.0
3 5.8 15.9 4 5.3 14.3 5 4.9 11.1
[0263] Capsules can be made of materials well-known in the art,
such as gelatin or hydroxypropyl methylcellulose. In one
embodiment, the capsule is made of a material that dissolves in the
gastric environment, but not in the oral or esophageal environment,
which prevents premature release of the system prior to reaching
the stomach.
[0264] In one embodiment, the system will be folded or compressed
into a compacted state in order to fit into the capsule, for
example, in a manner such as that shown in FIG. 1B. Once the
capsule dissolves in the stomach, the system will adopt a
configuration suitable for gastric retention, for example, in a
manner such as that shown in FIG. 1A. Preferred capsule sizes are
00 and 00el (a 00el-size capsule has the approximate length of a
000 capsule and the approximate width of a 00 capsule), which then
places constraints on the length and diameter of the folded
system.
[0265] Once released from the container, the system adopts an
uncompacted state with dimensions suitable to prevent passage of
the gastric residence system through the pyloric sphincter. In one
embodiment, the system has at least two perpendicular dimensions,
each of at least 2 cm in length; that is, the gastric residence
system measures at least about 2 cm in length over at least two
perpendicular directions. In another embodiment, the perimeter of
the system in its uncompacted state, when projected onto a plane,
has two perpendicular dimensions, each of at least 2 cm in length.
The two perpendicular dimensions can independently have lengths of
from about 2 cm to about 7 cm, about 2 cm to about 6 cm, about 2 cm
to about 5 cm, about 2 cm to about 4 cm, about 2 cm to about 3 cm,
about 3 cm to about 7 cm, about 3 cm to about 6 cm, about 3 cm to
about 5 cm, about 3 cm to about 4 cm, about 4 cm to about 7 cm,
about 4 cm to about 6 cm, about 4 cm to about 5 cm, or about 4 cm
to about 4 cm. These dimensions prevent passage of the gastric
residence system through the pyloric sphincter. For star-shaped
polymers with N arms (where N is greater than or equal to three,
such as N=6), the arms can have dimensions such that the system has
at least two perpendicular dimensions, each of length as noted
above. These two perpendicular dimensions are chosen as noted above
in order to promote retention of the gastric residence system.
[0266] The system is designed to eventually break apart in the
stomach at the end of the desired residence time (residence
period), at which point the remaining components of the system are
of dimensions that permit passage of the system through the pyloric
sphincter, small intestine, and large intestine. Finally, the
system is eliminated from the body by defecation, or by eventual
complete dissolution of the system. In the small and large
intestines. Thus, coupling polymers or disintegrating matrices are
placed in the gastric residence systems of the invention in a
configuration such that, at the end of the desired residence period
when the coupling polymers or disintegrating matrices break or
dissolve, the uncoupled components of the gastric residence system
have dimensions suitable for passage through the pyloric sphincter
and elimination from the digestive tract.
System Polymeric Composition
[0267] The choice of the individual polymers for the carrier
polymer, coupling polymer, and elastomer influence many properties
of the system, such as drug elution rate (dependent on the carrier
polymer, as well as other factors), the residence time of the
system (dependent on the degradation of any of the polymers,
principally the coupling polymers), the uncoupling time of the
system if it passes into the intestine (dependent primarily on the
enteric degradation rate of the coupling polymer, as discussed
herein), and the shelf life of the system in its compressed form
(dependent primarily on properties of the elastomer). As the
systems will he administered to the gastrointestinal tract, all of
the system components should be biocompatible with the
gastrointestinal environment.
[0268] The rate of elution of drug from the carrier polymer-drug
component is affected by numerous factors, including the
composition and properties of the carrier polymer, which may itself
be a mixture of several polymeric and non-polymeric components; the
properties of the drug such as hydrophilicity/hydrophobicity,
charge state, pKa, and hydrogen bonding capacity; and the
properties of the gastric environment. In the aqueous environment
of the stomach, avoiding burst release of a drug (where burst
release refers to a high initial delivery of active pharmaceutical
ingredient upon initial deployment of the system in the stomach),
particularly a hydrophilic drug, and maintaining sustained release
of the drug over a period of time of days to one or two weeks is
challenging.
[0269] The residence time of the systems in the stomach is adjusted
by the choice of coupling polymers used in the linker regions. The
systems will eventually break down in the stomach, despite the use
of enteric coupling polymers, as the mechanical action of the
stomach and fluctuating pH will eventually weaken the enteric
coupling polymers. Coupling polymers which degrade in a
time-dependent manner in the stomach can also be used to adjust the
time until the system breaks apart, and hence adjust the residence
time. Once the system breaks apart, it passes into the intestines
and is then eliminated.
[0270] The elastomer used in the systems is central to the shelf
life of the systems. When the systems are compressed, the elastomer
is subjected to mechanical stress. The stress in turn can cause
polymer creep, which, if extensive enough, can prevent the systems
from returning to their uncompacted configurations when released
from the capsules or other container; this in turn would lead to
premature passage of the system from the stomach. Polymer creep can
also be temperature dependent, and therefore the expected storage
conditions of the systems also need to be considered when choosing
the elastomer and other polymer components.
[0271] The system components and polymers should not swell, or
should have minimal swelling, in the gastric environment. The
components should swell no more than about 20%, no more than about
10%, or preferably no more than about 5% when in the gastric
environment over the period of residence.
Methods of Manufacture of Carrier Polymer-Agent (or Agent Salt)
Components
[0272] Blending temperatures for incorporation of the agent (or a
pharmaceutically acceptable salt thereof) into polymeric matrices
typically range from about 80.degree. C. to about 120.degree. C.,
although higher or lower temperatures can be used for polymers
which are best blended at temperatures outside that range. When
agent (or salt thereof) particles of a particular size are used,
and it is desired that the size of the particles be maintained
during and after blending, blending can be done at temperatures
below the melting point of the agent (or salt thereof), so as to
maintain the desired size of the particles. Otherwise, temperatures
can be used which melt both the polymer and the agent (or salt
thereof). Blending temperatures should be below the degradation
temperature of the agent (or salt thereof). In one embodiment, less
than about 2% of the agent (or salt thereof) is degraded during
manufacture. In one embodiment, less than about 1.5% of the agent
(or salt thereof) is degraded during manufacture. In one
embodiment, less than about 1% of the agent (or salt thereof) is
degraded during manufacture. In one embodiment, less than about
0.75% of the agent (or salt thereof) is degraded during
manufacture. In one embodiment, less than about 0.5% of the agent
(or salt thereof) is degraded during manufacture. In one
embodiment, less than about 0.4% of the agent (or salt thereof) is
degraded during manufacture. In one embodiment, less than about
0.3% of the agent (or salt thereof) is degraded during manufacture.
In one embodiment, less than about 0.2% of the agent (or salt
thereof) is degraded during manufacture. In one embodiment, less
than about 0.15% of the agent (or salt thereof) is degraded during
manufacture. In one embodiment, less than about 0.1% of the agent
(or salt thereof) is degraded during manufacture. In one
embodiment, less than about 0.05% of the agent (or salt thereof) is
degraded during manufacture. In one embodiment, less than about
0.04% of the agent (or salt thereof) is degraded during
manufacture. In one embodiment, less than about 0.03% of the agent
(or salt thereof) is degraded during manufacture. In one
embodiment, less than about 0.02% of the agent (or salt thereof) is
degraded during manufacture. In one embodiment, less than about
0.01% of the agent (or salt thereof) is degraded during
manufacture.
[0273] Hot melt extrusion can be used to prepare the carrier
polymer-agent (or agent salt) components. Single-screw or,
preferably, twin-screw systems can be used. As noted, if it is
desired that the size of the particles be maintained during and
after blending, carrier polymers should be used which can be melted
at temperatures which do not degrade the agent or salt thereof.
Otherwise, temperatures can be used which melt both the polymer and
the agent or salt thereof.
[0274] Melting and casting can also be used to prepare the carrier
polymer-agent (or salt thereof) components. The carrier polymer and
agent (or salt thereof), and any other desired components, are
mixed together. The carrier polymer is melted and the melt is mixed
so that the agent (or salt thereof) particles are evenly
distributed in the melt, poured into a mold, and allowed to
cool.
[0275] Solvent casting can also be used to prepare the carrier
polymer-agent (or salt thereof) components. The polymer is
dissolved in a solvent, and particles of agent (or salt thereof)
are added. If the size of the agent (or salt thereof) particles are
to be maintained, a solvent should be used which does not dissolve
the agent (or salt thereof) particles, so as to avoid altering the
size characteristics of the particles; otherwise, a solvent which
dissolves both the polymer and agent (or salt thereof) particles
can be used. The solvent-carrier polymer-agent (or salt thereof)
particle mixture (or solvent-carrier particle-agent/agent salt
solution), is then mixed to evenly distribute the particles (or
thoroughly mix the solution), poured into a mold, and the solvent
is evaporated.
Manufacture/Assembly of System: Affixing Elongate Members to
Central Elastomer
[0276] For a stellate gastric residence system, such as that shown
in FIG. 1A, the elongate members, or "arms" of the gastric
residence system can be affixed to the central elastomer in a
number of ways. The central polymer can be cast or molded with
short "asterisk" arms, and a linker polymer can be used to affix
the elongate members to the asterisk arms of the central elastomer.
Alternatively, the central elastomer can be formed in a mold into
which the proximal ends of the elongate members protrude. The
elastomer sets, cures, or otherwise hardens into its desired form
with a portion of the elongate members extending into the body of
the central elastomer. Alternatively, the central elastomer can be
prepared with cavities into which the elongate members can be
firmly inserted.
[0277] The invention thus includes a method of making a gastric
residence system, comprising preparing at least three elongate
members formed from a material comprising any drug-carrier
polymer-excipient formulation as disclosed herein; and attaching
the elongate members to a central elastomer to form a gastric
residence system. The elongate members can comprise at least one
segment with a release rate-controlling polymer film. The elongate
members of the gastric residence system project radially from the
central elastomer, such as in a "hub and spoke" arrangement. A
preferred number of elongate members or "arms" is six. However,
stellate systems with three, four, five, seven, or eight elongate
members can also be used.
[0278] In some embodiments, elongate members or "arms" comprising
any carrier polymer-agent formulation, including arms comprising
segments having release rate-modulating polymer films, can be
heat-welded, solvent-welded, or otherwise affixed to other
elements, including disintegrating matrices, coupling polymers, or
interfacing polymers, which are then affixed to a central
elastomer. In some embodiments, the arms are directly affixed to a
central elastomer. Disintegrating matrices, coupling polymers, or
interfacing polymer segments can be welded or otherwise affixed to
the central elastomer prior to affixing the elongate members.
[0279] In some embodiments, arms comprising any drug-carrier
polymer-excipient formulation as disclosed herein can be
heat-welded to polycaprolactone segments, such as short
polycaprolactone "asterisk" arms affixed to a central elastomer.
Linker segments can be welded to the short "asterisk" arms prior to
affixing the drug-carrier polymer-excipient formulation arms. Heat
welding of drug-carrier polymer-excipient formulation arms to MW
80,000 PCL segments at temperatures between 140.degree. C. to
170.degree. C., followed by cooling for 24 hours at 8.degree. C.,
resulted in stronger welds. Thus, in one embodiment, attaching the
elongate members comprising any drug-carrier polymer-excipient
formulation as disclosed herein to a central elastomer to form a
gastric residence system, can comprise heat-welding the elongate
members to other system components, such as asterisk arms or other
segments comprising at least about 90%, at least about 95%, or at
least about 99% polycaprolactone (such as MW 80,000 PCL), at a
temperature between about 140.degree. C. to about 170.degree. C.,
followed by cooling of the welded members attached to other system
components for about 12 to about 48 hours at a temperature of about
2.degree. C. to about 14.degree. C., such as about 5.degree. C. to
about 10.degree. C., or about 8.degree. C. The other system
components can alternatively be linker elements.
Manufacture/Assembly of System
[0280] Once the elongate members of the gastric residence system
have been affixed to the central elastomer, the system is ready to
be folded into its compacted configuration and placed into a
capsule for storage, transport, and eventual administration. The
system can be folded in an automated mechanical process, or by
hand, and placed into a capsule of the appropriate size and
material. More detail regarding manufacture and assembly of gastric
residence systems, and of packaging the gastric residence system
into capsules, can be found in International Patent Application
Nos. WO 2015/191920, WO 2015/191925, WO 2017/070612, WO
2017/100367, and. PCT/US2017/034856.
Carrier Polymer-Agent/Release Rate-Modulating Film Combinations
[0281] A variety of carrier polymer-agent segment formulations can
be used with any given release rate-modulating film to provide
desired release characteristics from the film-coated segment.
Likewise, a variety of release rate-modulating films can be used
with any given carrier polymer-agent segment formulation. One
useful combination of carrier polymer-agent/film comprises a
segment with about 15% to about 40% agent, about 3% to about 15% of
excipients selected from one or more of P407, silica, and vitamin E
succinate, with the balance of the segment made up of
polycaprolactone (PCL); and a release rate-modulating film that is
about 75% to about 95% polycaprolactone with the balance of the
film comprising copovidone porogen, where the weight of the film is
about 0.5% to about 2% of the weight of the underlying segment,
and/or where the thickness of the film ranges from about 3 microns
to about 10 microns. An exemplary combination is 27.5% agents, 6%
excipients (P407, silica, vitamin E succinate), and 66.5% PCL, with
a film that is 90% PCL 10% copovidone porogen, where the weight of
the film is about 1% of the weight of the underlying segment.
[0282] Another useful combination of carrier polymer-agent/film
comprises a segment with about 30% to about 50% agent, about 10% to
about 30% plasticizer, about 0% to about 10% of excipients selected
from one or more of P407, silica, and vitamin E succinate, with the
balance of the segment made up of polycaprolactone (PCL); and a
release rate-modulating film that is about 75% to about 95%
polycaprolactone with the balance of the film comprising copovidone
porogen, where the weight of the film is about 0.5% to about 3% of
the weight of the underlying segment, and/or where the thickness of
the film ranges from about 3 microns to about 12 microns.
Methods of Treatment Using the Gastric Residence Systems
[0283] The gastric residence systems can be used to treat
conditions requiring administration of a drug or agent over an
extended period of time. In a preferred embodiment, a gastric
residence system is administered to a human. For long-term
administration of agents or drugs which are taken for months,
years, or indefinitely, administration of a gastric residence
system periodically, such as once weekly or once every two weeks
can provide substantial advantages in patient compliance and
convenience. Accordingly, the gastric residence systems of the
invention can be administered once every three days, once every
five days, once weekly, once every ten days, or once every two
weeks. The administration frequency is timed to coincide with the
designed gastric residence period of the gastric residence system
which is administered, so that at about the same time that a
gastric residence system passes out of the stomach after its
residence period, a new gastric residence system is
administered.
[0284] Once a gastric residence system has been administered to a
patient, the system provides sustained release of agent or drug
over the period of gastric retention. After the period of gastric
retention, the system degrades and passes out of the stomach. Thus,
for a system with a gastric retention period of one week, the
patient will swallow (or have administered to the stomach via other
methods) a new system every week. Accordingly, in one embodiment, a
method of treatment of a patient with a gastric retention system of
the invention having a gastric residence period of a number of days
D (where D-days is the gastric residence period in days), over a
total desired treatment period T-total (where T-total is the
desired length of treatment in days) with the agent or drug in the
system, comprises introducing a new gastric residence system every
D-days into the stomach of the patient, by oral administration or
other methods, over the total desired treatment period. The number
of gastric residence systems administered to the patient will be
(T-total) divided by (D-days). For example, if treatment of a
patient for a year (T-total 365 days) is desired, and the gastric
residence period of the system is 7 days (D-days=7 days),
approximately 52 gastric residence systems will be administered to
the patient over the 365 days, as a new system will be administered
once every seven days.
[0285] Alternatively, the patient can swallow (or have administered
to the stomach via other methods) a new gastric residence system at
the end of the effective release period of the gastric residence
system. The "effective release period" or "effective release time"
is the time over which the gastric residence system releases an
effective amount of the agent contained in the system. Accordingly,
in one embodiment, a method of treatment of a patient with a
gastric residence system of the invention having an effective
release period of a number of days E (where E-days is the effective
release period in days), over a total desired treatment period
T-total (where T-total is the desired length of treatment in days)
with the agent in the system, comprises introducing a new gastric
residence system every E-days into the stomach of the patient, by
oral administration or other means, over the total desired
treatment period. The number of gastric residence systems
administered to the patient will be (I-total) divided by (E-days).
For example, if treatment of a patient for a year (T-total=365
days) is desired, and the effective release period of the system is
7 days (E-days=7 days), approximately 52 gastric residence systems
will be administered to the patient over the 365 days, as a new
system will be administered once every seven days.
Gastric Delivery Pharmacokinetics for Gastric Residence Systems
[0286] The gastric residence systems of the invention provide for
high bioavailability of the agent as measured by AUC.sub.inf after
administration of the systems, relative to the bioavailability of a
conventional oral formulation of the agent. The systems also
provide for maintenance of an approximately constant plasma level
or a substantially constant plasma level of the agent.
[0287] Relative bioavailability, F.sub.REL, of two different
formulations, formulation A and formulation B, is defined as:
F.sub.REL=100.times.(AUC.sub.A.times.Dose.sub.B)/(AUC.sub.B.times.Dose.s-
ub.A)
where AUC.sub.A is the area under the curve for formulation A,
AUC.sub.B is the area under the curve for formulation B, Dose.sub.A
is the dosage of formulation A used, and Dose.sub.B is the dosage
of formulation B used. AUC, the area under the curve for the plot
of agent plasma concentration versus time, is usually measured at
the same time (t) after administration of each formulation, in
order to provide the relative bioavailability of the formulations
at the same time point. AUC.sub.inf refers to the AUC measured or
calculated over "infinite" time, that is, over a period of time
starting with initial administration, and ending where the plasma
level of the agent has dropped to a negligible amount.
[0288] In one embodiment, the substantially constant plasma level
of agent provided by the gastric residence systems of the invention
can range from at or above the trough level of the plasma level of
agent when administered daily in a conventional oral formulation
(that is, C.sub.min of agent administered daily in
immediate-release formulation) to at or below the peak plasma level
of agent when administered daily in a conventional oral formulation
(that is, C.sub.max of agent administered daily in
immediate-release formulation). In some embodiments, the
substantially constant plasma level of agent provided by the
gastric residence systems of the invention can be about 50% to
about 90% of the peak plasma level of agent when administered daily
in a conventional oral formulation (that is, C.sub.max of agent
administered daily in immediate-release formulation). The
substantially constant plasma level of agent provided by the
gastric residence systems of the invention can be about 75% to
about 125% of the average plasma level of agent when administered
daily in a conventional oral formulation (that is, C.sub.ave of
agent administered daily in immediate-release formulation). The
substantially constant plasma level of agent provided by the
gastric residence systems of the invention can be at or above the
trough level of plasma level of agent when administered daily in a
conventional oral formulation (that is, C.sub.min of agent
administered daily in immediate-release formulation), such as about
100% to about 150% of C.sub.min.
[0289] The gastric residence systems of the invention can provide
bioavailability of agent released from the system of at least about
50%, at least about 60%, at least about 70%, or at least about 80%
of that provided by an immediate release form comprising the same
amount of agent. As indicated above, the bioavailability is
measured by the area under the plasma concentration-time curve
(AUCini).
Dissolution Profile, Bioavailability and Pharmacokinetics for
Gastric Residence Systems
[0290] Dissolution: The gastric residence systems described herein
provide a steady release of an agent or a pharmaceutically
acceptable salt thereof over an extended period of time. The
systems are designed to release a therapeutically effective amount
of an agent or salt thereof over the period of residence in the
stomach. The release of agent (or salt thereof) can be measured in
vitro or in vivo to establish the dissolution profile (elution
profile, release rate) of the agent (or salt thereof) from a given
residence system. In a specific environment. The dissolution
profile can be specified as a percentage of the original amount of
agent (or salt thereof) present in the system which elutes from the
system over a given time period.
[0291] Thus, in some embodiments, the agent (or salt thereof)
contained in a gastric residence system can have a dissolution
profile of 10-20% release between zero hours and 24 hours in a
given environment. That is, over the 24-hour period after initial
introduction of the gastric residence system into the environment
of interest, 10-20% of the initial agent (or salt thereof)
contained in the system elutes from the system.
[0292] The environment of interest can be I) the stomach of a
patient (that is, an in vivo environment), or 2) simulated gastric
fluid (that is, an in vitro environment).
[0293] The gastric residence systems of the invention provide for
high bioavailability of the agent (or salt thereof) as measured by
AUC.sub.inf after administration of the systems, relative to the
bioavailability of a conventional oral formulation of the agent (or
salt thereof). The systems also provide for maintenance of a
substantially constant plasma level of the agent (or salt
thereof).
[0294] Parameters of interest for release include the linearity of
release over the residence period of the gastric residence systems,
the standard deviation of release over the residence period (which
is related to linearity of release; a standard deviation of zero
indicates that release is linear over the entire residence period),
the release over the initial six hours of residence (that is, burst
release upon initial administration), and total release of agent
(or salt thereof) over the residence period. A preferable residence
period is seven days, although other periods, such as two, three,
four, five, six, eight, nine, ten, 11, 12, 13, or 14 days can be
useful.
[0295] Linearity of agent (or salt thereof) release over the
residence period refers to the amount released during each 24-hour
period of residence. For a seven-day period of residence, it is
desirable that about the amount of agent (or salt thereof) is
released each day, i.e., that linearity of agent (or salt thereof)
release is maximized. This will minimize the standard deviation of
daily agent or agent salt release over the residence period. In
some embodiments, the gastric release systems have a variation (or
a standard deviation) for daily agent (or salt thereof) release of
less than about 100%, less than about 90%, less than about 80%,
less than about 70%, less than about 60%, less than about 50%, less
than about 40%, less than about 30%, less than about 25%, less than
about 20%, less than about 15%, less than about 10%, or less than
about 5%, over the period of residence. In some embodiments, the
period of residence can be about three days, about seven days,
about ten days, or about two weeks.
[0296] Minimization of burst release, that is, release over the
initial period of residence (such as six hours, twelve hours, or 24
hours after administration of a gastric residence system) is
desirable in order to maintain a predictable and steady release
profile. If T is the total agent (or salt thereof) release over the
residence period units of mass), and D is the number of days of the
residence period, then completely linear release would mean that
about T/D mass of agent (or salt thereof) is released per day. If
the period over which burst release is measured is the first six
hours, then a linear release profile will result in 0.25.times.T/D
mass of agent (or salt thereof) released during the first six
hours. In percentage terms of the total amount of agent (or salt
thereof) released over the residence period of D days, linear
release would be about 100D % of agent (or salt thereof) per day,
and a linear release over the first six hours would be 25/D %.
(Note that 100% in this context indicates the total amount of agent
(or salt thereof) released, regardless of how much agent (or salt
thereof) is contained in the initial formulation.) Thus, for a
seven day residence period, linear release over the first six hours
would be about 3.6% of the total amount of agent (or salt thereof)
released over the seven-day period.
[0297] In some embodiments, during the initial six hours of
residence after administration the gastric residence systems
release about 0.2 to about 2 times T/D of the total mass of agent
(or salt thereof) T released over the residence period of D days,
or about 0.2 to about 1.75 times T/D of the total mass of agent (or
salt thereof) T released over the residence period of D days, or
about 0.2 to about 1.5 times T/D of the total mass of agent (or
salt thereof) T released over the residence period of D days, or
about 0.2 to about 1.25 times T/D of the total mass of agent (or
salt thereof) T released over the residence period of D days, or
about 0.2 to about 1 times T/D of the total mass of agent (or salt
thereof) T released over the residence period of D days, or about
0.2 to about 0.8 times T/D of the total mass of agent (or salt
thereof) T released over the residence period of D days, or about
0.2 to about 0.75 times T/D, or about 0.2 to about 0.7 times T/D,
or about 0.2 to about 0.6 times T/D, or about 0.2 to about 0.5
times T/D, or about 0.2 to about 0.4 times T/D, or about 0.2 to
about 0.3 times T/D, or about 0.25 to about 2 times T/D, or about
0.3 to about 2 times T/D, or about 0.4 to about 2 times T/D, or
about 0.5 to about 2 times T/D, or about 0.6 to about 2 times T/D,
or about 0.7 to about 2 times T/D, or about 0.25 to about 1.5 times
T/D, or about 0.3 to about 1.5 times T/D, or about 0.4 to about 1.5
times T/D, or about 0.5 to about 1.5 times T/D, or about 0.6 to
about 1.5 times T/D, or about 0.7 to about 1.5 times T/D, or about
0.25 to about 1.25 times T/D, or about 0.3 to about 1.25 times T/D,
or about 0.4 to about 1.25 times T/D, or about 0.5 to about 1.25
times T/D, or about 0.6 to about 1.25 times T/D, or about 0.7 to
about 1.25 times T/D, or about 0.25 to about 1 times T/D, or about
0.3 to about 1 times T/D, or about 0.4 to about 1 times T/D, or
about 0.5 to about 1 times T/D, or about 0.6 to about 1 times T/D,
or about 0.7 to about 1 times T/D, or about 0.25 times T/D, or
about 0.25 to about 0.8 times T/D, or about 0.3 to about 0.8 times
T/D, or about 0.4 to about 0.8 times T/D, or about 0.5 to about 0.8
times or about 0.6 to about 0.8 times T/D, or about 0.7 to about
0.8 times T/D, or about 0.8 times T/D, about 1 times T/D, about
1.25 times T/D, about 1.5 times T/D, or about 2 times T/D.
[0298] In some embodiment of the gastric residence systems, during
the initial six hours of residence after administration the gastric
residence systems release about 2% to about 10% of the total mass
of agent (or salt thereof) released over the residence period, or
about 3% to about 10%, or about 4% to about 10%, or about 5% to
about 10%, or about 6% to about 10%, or about 7% to about 10%, or
about 8% to about 10%, or about 9% to about 10%, or about 2% to
about 9%, or about 2% to about 8%, or about 2% to about 7%, or
about 2% to about 6%, or about 2% to about 5%, or about 2% to about
4%, or about 2% to about 3%.
[0299] In some embodiments of the gastric residence systems, where
the gastric residence systems have a residence period of about
seven days, during the initial six hours of residence after
administration the gastric residence systems release about 2% to
about 10% of the total mass of agent (or salt thereof) released
over the residence period of seven days, or about 3% to about 10%,
or about 4% to about 10%, or about 5% to about 10%, or about 6% to
about 10%, or about 7% to about 10%, or about 8% to about 10%, or
about 9% to about 10%, or about 2% to about 9%, or about 2% to
about 8%, or about 2% to about 7%, or about 2% to about 6%, or
about 2% to about 5%, or about 2% to about 4%, or about 2% to about
3%.
[0300] In some embodiments, during the initial 24 hours of
residence after administration, the gastric residence systems
release about 10% to about 35% of the total mass of agent (or salt
thereof) released over the residence period, or about 10% to about
30%, or about 10% to about 25%, or about 10% to about 20%, or about
10% to about 15%, or about 15% to about 35%, or about 15% to about
35%, or about 15% to about 30%, or about 20% to about 30%, or about
25% to about 35%, or about 25% to about 30%, or about 30% to about
35%.
[0301] In some embodiments, where the gastric residence systems
have a residence period of about seven days, during the initial 24
hours of residence after administration the gastric residence
systems release about 10% to about 35% of the total mass of agent
(or salt thereof) released over the residence period of seven days,
or about 10% to about 30%, or about 10% to about 25%, or about 10%
to about 20%, or about 10% to about 15%, or about 15% to about 35%,
or about 15% to about 35%, or about 15% to about 30%, or about 20%
to about 30%, or about 25% to about 35%, or about 25% to about 30%,
or about 30% to about 35%.
Reduction of pH Effect on Release Rate
[0302] The gastric residence systems, and segments of gastric
residence systems, as described herein which comprise release-rate
modulating polymer films have reduced variability of release of an
agent or pharmaceutically acceptable salt thereof at different pH
values, as compared to release from gastric residence systems or
segments of gastric residence systems of similar composition but
which lack the release-rate modulating polymer films.
[0303] The solubility of certain agents, or salts thereof, can vary
at different pH values. For example, the solubility of risperidone
is significantly higher at the more acidic end of the gastric pH
range (e.g., pH 1.5) than at the less acidic end of the gastric pH
range (e.g., pH 4.8). Risperidone will thus have a faster
dissolution rate at the lower pH, and will have a tendency to be
released faster from a gastric residence system at the lower pH.
Since the pH of the stomach can vary over time due to several
factors, reducing the variation in release rate of a given agent or
salt thereof at different pH values aids in providing a linear
dissolution profile over a given period of time.
[0304] The pH-dependent release rate ratio, RR.sub.pH, for a given
agent or salt thereof at a given first pH value and a given second
pH value can be expressed as:
RR.sub.pH=(rate of release at a first pH) divided by (rate of
release at a second pH).
If the rates of release at the first and second pH are identical,
the RR.sub.pH will be 1. If the rate of release at the first pH is
higher than the rate of release at the second pH, the RR.sub.pH
will be greater than 1, while if the rate of release at the first
pH is lower than the rate of release at the second pH, the
RR.sub.pH will be less than one. In order to reduce variability of
release at different pH values, a value of RR.sub.pH as close to 1
as possible is desirable.
[0305] A pH-dependent release rate ratio factor, RRF.sub.pH, can be
defined as the factor by which the release rate at the two pH
values differ. RRF.sub.pH is the same as RR.sub.pH when RR.sub.pH
is greater than one, and is the reciprocal of RR.sub.pH when
RR.sub.pH is less than one.
[0306] Release rate ratios for gastric residence systems can be
measured at any two different pH values between about 1 and about
6, and generally at pH values at least about 1 pH unit apart, such
as at least about 2 pH units apart, at least about 3 pH units
apart, or at least about 4 pH units apart. Two useful values are a
first pH of about 1.5 and a second pH of about 4.8, to represent
typical low-pH and high-pH extremes of stomach pH. Release rate
ratios can be measured in simulated gastric fluid adjusted to the
pH of interest, such as FaSSGF, including FaSSGF at about pH 1 to
pH 2, e.g. at pH 1.5. Release rate ratios can also be measured in
buffer systems at the pH of interest, such as ammonium acetate (for
example, at about pH 4.8). Release rate ratios can be calculated by
measuring release from gastric residence systems at two different
pH values over a period of time, such as about one hour, about two
hours, about three hours, about six hours, about 12 hours, about 24
hours, about 48 hours, about 72 hours, about 96 hours, about 5
days, about 6 days, about 7 days, about 8 days, about 9 days, about
10 days, or about 2 weeks.
[0307] The gastric residence systems and the segments of gastric
residence systems described herein, comprising a release-rate
modulating film, can have a pH-dependent release rate ratio factor
RRF.sub.pH, where the first pH is 1.5 and the second pH is 4.8, or
alternatively where the first pH and the second pH are both between
about pH 1 and about pH 6 and are at least about 3 pH units apart,
of greater than about 1, of greater than about 2, of greater than
about 3, of greater than about 4, of greater than about 5, of
greater than about 6, of greater than about 10, of greater than
about 20, or of about 1 to about 20, of about 1 to about 10, of
about 1 to about 6, of about 1 to about 4, of about 1 to about 3,
of about 1 to about 2.5, about 1 to about 2.2, about 1 to about 2,
about 1 to about 1.9, about 1 to about 1.8, about 1 to about 1.7,
about 1 to about 1.6, about 1 to about 1.5, about 1 to about 1.4,
about 1 to about 1.3, about 1 to about 1.2, about 1 to about 1.1,
about 1.1 to about 2, about 1.2 to about 2, about 1.3 to about 2,
about 1.4 to about 2, or about 1.5 to about 2.
[0308] The gastric residence systems and the segments of gastric
residence systems described herein, comprising a release-rate
modulating film, can have a pH-dependent release rate ratio
RR.sub.pH, where the first pH is about 1.5 and the second pH is
about 4.8, or alternatively where the first pH and the second pH
are both between about pH 1 and about pH 6 and are at least about 3
pH units apart, of about 0.05 to about 20, of about 0.1 to about
10, of about 0.2 to about 5, of about 0.25 to about 4, about 0.3 to
about 3, 0.4 to about 2.5, about 0.5 to about 2, about 0.6 to about
2, about 0.7 to about 2, about 0.8 to about 2, about 0.9 to about
2, about 1 to about 20, about 1 to about 10, about 1 to about 5,
about 1 to about 4, about 1 to about 3, about 1 to about 2, about
1.1 to about 2, about 1.2 to about 2, about 1.3 to about 2, about
1.4 to about 2, or about 1.5 to about 2. The gastric residence
systems and the segments of gastric residence systems described
herein, comprising a release-rate modulating film, can have a
pH-dependent release rate ratio RR.sub.pH, where the first pH is
1.5 and the second pH is 4.8, or alternatively where the first pH
and the second pH are both between about pH 1 and about pH 6 and
are at least about 3 pH units apart, of about 1 to about 2.5, about
1 to about 2.2, about 1 to about 2, about 1 to about 1.9, about 1
to about 1.8, about 1 to about 1.7, about 1 to about 1.6, about 1
to about 1.5, about 1 to about 1.4, about 1 to about 1.3, about 1
to about 1.2, or about 1 to about 1.1; or of greater than about 1,
greater than about 1.5, greater than about 2, greater than about 3,
greater than about 4, greater than about 5, greater than about 10,
or greater than about 20. The gastric residence systems and the
segments of gastric residence systems described herein, comprising
a release-rate modulating film, can have a pH-dependent release
rate ratio RR.sub.pH, where the first pH is 1.5 and the second pH
is 4.8, or alternatively where the first pH and the second pH are
both between about pH 1 and about pH 6 and are at least about 3 pH
units apart, of about 0.05 to about 1 of about 0.1 to about 1, of
about 0.25 to about 1, about 0.3 to about 1, about 0.4 to about 1,
about 0.5 to about 1. about 0.6 to about 1, about 0.7 to about 1,
about 0.8 to about 1, or about 0.9 to about 1; or of less than
about 0.9, less than about 0.8, less than about 0.7, less than
about 0.6, less than about 0.5, less than about 0.4, less than
about 0.3, less than about 0.2, less than about 0.1, or less than
about 0.05.
[0309] pH-dependent release rate ratios of agents and
pharmaceutically acceptable salts thereof from gastric residence
systems tend to deviate from the ideal value of one when there is a
significant difference in solubility of an agent or salt thereof at
different pH values. The difference in solubility of an agent or a
pharmaceutically acceptable salt thereof at two different pH values
used in the gastric residence systems described herein can be about
a factor of about 1.25 or more, a factor of about 1.5 or more, a
factor of about 3 or more, a factor of about 4 or more, a factor of
about 5 or more, a factor of about 10 or more, a factor of about 20
or more, a factor of about 30 or more, a factor of about 40 or
more, a factor of about 50 or more, a factor of about 75 or more,
or a factor of about 100 or more; or a factor of about 2 to about
100, about 2 to about 75, about 2 to about 50, about 2 to about 20,
about 2 to about 10, about 5 to about 100, about 5 to about 75,
about 5 to about 50, about 5 to about 20, or about 5 to about 10,
where the two different pH values lie between about pH 1 and about
pH 6, such as about pH 1.5 and about pH 4.8, or where the first pH
and the second pH are at least about 3 pH units apart. Generally,
the greater the difference in solubility of an agent or
pharmaceutically acceptable salt thereof at two different pH
values, the more useful release-rate modulating polymer films
become for reducing differences in pH-dependent rates of release
from gastric residence systems. For example, when the difference in
solubility of an agent or a pharmaceutically acceptable salt
thereof at two different pH values between about pH 1 and about pH
6 (such as about pH 1.5 and about pH 4.8) is a factor of about 5 or
more, or where the difference in solubility of an agent or a
pharmaceutically acceptable salt thereof at a first pH value and a
second pH value where the values are at least about 3 pH units
apart is a factor of about 5 or more (for example, an agent having
a solubility of 12 mg/ml at pH 1.5 and a solubility of 2 mg/ml at
pH 4.8 has a difference in solubility at the two different pH
values of a factor of 6), release-rate modulating polymer films are
very useful in reducing difference in pH-dependent rates of release
from gastric residence systems. However, release-rate modulating
polymer films can be used to shift the pH-dependent release rate
ratio closer to one when there is any difference in solubility of
an agent or a pharmaceutically acceptable salt thereof at two
different pH values, and release-rate modulating polymer films can
be used for the other purposes disclosed herein even if there is no
significant difference in solubility of an agent at different pH
values.
[0310] The release-rate modulating polymer films used for the
gastric residence systems and the segments of gastric residence
systems described herein, can reduce the deviation from the ideal
value of 1 in the pH-dependent release rate ratio factor RRF.sub.pH
of the gastric residence system as compared to the deviation in the
same gastric residence system lacking the release-rate modulating
films, by about 10%, about 25%, about 33%, about 50%, about 75%, or
by a factor of about 1.25, about 1.5, about 2, or about 3. The
deviation in pH-dependent release rate ratio factor RRF.sub.pH is
defined as (RRF.sub.pH-1), and can also be referred to as the
deviation from 1 of the pH-dependent release rate ratio factor
RRF.sub.pH. For example, if a first gastric residence system
lacking a release-rate modulating polymer film has a release rate
in arbitrary units of 9 at pH 1.5 and 3 at pH 4.8, its pH-dependent
release rate ratio factor RRF.sub.pH is (9/3)=3, and it deviates by
2 units from the ideal value of 1 (where release rates at the two
pH values are equal). If a second gastric residence system having
the same components as the first gastric residence system, but also
including a release-rate modulating polymer film, has a release
rate in arbitrary units of 4 at pH 1.5 and 2 at pH 4.8, its
pH-dependent release rate ratio factor RRF.sub.pH is (4/2)=2, which
deviates by 1 unit from the ideal value of 1. Thus, the
release-rate modulating polymer coating has reduced the deviation
of the pH-dependent release rate ratio factor RRF.sub.pH from the
ideal value by a factor of 2, since the deviation from the ideal
value for the system lacking the film was 2 units, and the
deviation from the ideal value for the system with the film was 1
unit.
Kits and Articles of Manufacture
[0311] Also provided herein are kits for treatment of patients with
the gastric residence systems of the invention. The kit may
contain, for example, a sufficient number of gastric residence
systems for periodic administration to a patient over a desired
total treatment time period. If the total treatment time in days is
(T-total), and the gastric residence systems have a residence time
of (D-days), then the kit will contain a number of gastric
residence systems equal to ((T-total) divided by (D-days) (rounded
to an integral number), for administration every D-days.
Alternatively, if the total treatment time in days is (T-total),
and the gastric residence systems have an effective release period
of (E-days), then the kit will contain a number of gastric
residence systems equal to ((T-total) divided by (E-days)) (rounded
to an integral number), for administration every E-days. The kit
may contain, for example, several gastric residence systems in
containers (where the containers may be capsules) and may
optionally also contain printed or computer readable instructions
for dosing regimens, duration of treatment, or other information
pertinent to the use of the gastric residence systems and/or the
agent or drug contained in the gastric residence systems. For
example, if the total treatment period prescribed for the patient
is one year, and the gastric residence system has a residence time
of one week or an effective release period of one week, the kit may
contain 52 capsules, each capsule containing one gastric residence
system, with instructions to swallow one capsule once a week on the
same day (e.g., every Saturday).
[0312] Articles of manufacture, comprising a sufficient number of
gastric residence systems for periodic administration to a patient
over a desired total treatment time period, and optionally
comprising instructions for dosing regimens, duration of treatment,
or other information pertinent to the use of the gastric residence
systems and/or the agent or drug contained in the gastric residence
systems, are also included in the invention. The articles of
manufacture may be supplied in appropriate packaging, such as
dispensers, trays, or other packaging that assists the patient in
administration of the gastric residence systems at the prescribed
interval.
EXEMPLARY EMBODIMENTS
[0313] The invention is further described by the following
embodiments. The features of each of the embodiments are combinable
with any of the other embodiments where appropriate and
practical.
[0314] Embodiment 1. A segment of a gastric residence system, the
segment comprising: a carrier polymer; an agent or a salt thereof;
and a release-rate modulating polymer film configured to control
the release rate of the agent or salt thereof, wherein over a
seven-day incubation of the segment in simulated gastric fluid, the
amount of the agent or salt thereof released from the segment
during day 5 is at least about 40% of the amount of agent or salt
thereof released during day 2; and wherein at least about 7% of the
total amount of agent or salt thereof in the segment is released on
day 2 and at least about 7% of the total amount of agent or salt
thereof is released on day 5.
[0315] Embodiment 2. A segment of a gastric residence system, the
segment comprising: a carrier polymer; an agent or a salt thereof;
and a release-rate modulating polymer film configured to control
the release rate of the agent or salt thereof, wherein over a
seven-day incubation of the segment in simulated gastric fluid, the
amount of the agent or salt thereof released from the segment
during day 7 is at least about 20% of the amount of agent or salt
thereof released during day 1; and wherein at least about 4% of the
total amount of agent or salt thereof in the segment is released on
day 1 and at least about 4% of the total amount of agent or salt
thereof is released on day 7.
[0316] Embodiment 3. A segment of a gastric residence system, the
segment comprising: a carrier polymer, an agent or a salt thereof
and a release-rate modulating polymer film configured to control
the release rate of the agent or salt thereof, wherein the
release-rate modulating polymer film is configured such that the
release of agent or salt thereof from the segment in 40%
ethanol/60% simulated gastric fluid over one hour is no more than
about 40% higher compared to release of agent or salt thereof from
an equivalent segment in 100% simulated gastric fluid over one
hour.
[0317] Embodiment 4. A segment of a gastric residence system, the
segment comprising: a carrier polymer, an agent or a salt thereof
and a release-rate modulating polymer film configured to control
the release rate of the agent or salt thereof, wherein the
release-rate modulating polymer film is configured such that the
release of agent or salt thereof from the segment in 40%
ethanol/60% simulated gastric fluid over one hour is at least about
40% lower than the release of agent or salt thereof from a second
segment in 40% ethanol/60%, simulated gastric fluid over one hour,
the second segment comprising the same combination of carrier
polymer and agent or salt thereof but lacking the release-rate
modulating polymer film.
[0318] Embodiment 5. A segment of a gastric residence system, the
segment comprising: a carrier polymer, an agent or a salt thereof
and a release-rate modulating polymer film configured to control
the release rate of the agent or salt thereof, wherein the
release-rate modulating polymer film is configured such that the
release of agent or salt thereof from the segment in simulated
gastric fluid over an initial 6 hour period is at least about 40%
lower than the release of agent or salt thereof from a second
segment in simulated gastric fluid over an initial 6 hour period,
the second segment comprising the same combination of carrier
polymer and agent or salt thereof but lacking the release-rate
modulating polymer film; and wherein the release of agent or salt
thereof from the segment in simulated gastric fluid over a
seven-day period is at least about 60% of the total amount of agent
or salt thereof originally present in the segment.
[0319] Embodiment 6. The segment of embodiment 5, wherein the
release of agent or salt thereof from the segment in simulated
gastric fluid over a seven-day period is at least about 70% of the
release of the total amount of agent or salt thereof originally
present in the segment.
[0320] Embodiment 7. The segment of embodiment 5, wherein the
release of agent or salt thereof from the segment in simulated
gastric fluid over a seven-day period is at least about 80% of the
release of the total amount of agent or salt thereof originally
present in the segment.
[0321] Embodiment 8. A segment of a gastric residence system, the
segment comprising: a carrier polymer; an agent or a salt thereof
and a release-rate modulating, polymer film, wherein the polymer
film is configured to control the release rate of the agent or salt
thereof such that a best-fit linear regression model of the release
rate of agent or salt thereof from the segment in simulated gastric
fluid has a coefficient of determination R.sup.2 of at least about
0.8 over an initial period of seven days; and wherein the segment
releases about 40% to about 60% of the agent or salt thereof within
a time of about 40% to about 60% of the seven-day period.
[0322] Embodiment 9. The segment of embodiment 8, wherein the
polymer film is configured to control the release rate of the agent
or salt thereof such that a best-fit linear regression model of the
release rate of agent or salt thereof from the segment in simulated
gastric fluid has a coefficient of determination R.sup.2 of at
least about 0.9 over an initial period of seven days; and wherein
the segment releases about 40% to about 60% of the agent or salt
thereof within a time of about 40% to about 60% of the seven-day
period.
[0323] Embodiment 10. A segment of a gastric residence system, the
segment comprising: a earlier polymer; an agent or a salt thereof;
and a release-rate modulating polymer film, wherein the polymer
film is configured to control the release rate of the agent or salt
thereof from the segment over a seven-day period in simulated
gastric fluid such that the release rate from the segment over any
one of the seven days varies by no more than about 25% from the
average daily total release from the segment over the seven
days.
[0324] Embodiment 11. The segment of a gastric residence system
according to any one of embodiments 1-10, wherein the release-rate
modulating polymer film comprises one or more polyester
materials.
[0325] Embodiment 12. The segment of embodiment 11, wherein the
polymer film comprises polyester with a repeating unit of the
form:
--R.sup.1--O--C(.dbd.O)--
wherein R.sup.1 is selected from the group consisting of
C.sub.1-C.sub.12 alkylene groups, ethers containing between two and
twelve carbon atoms, and polyethers containing between three and
twelve carbon atoms.
[0326] Embodiment 13. The segment of embodiment 11, wherein the
polymer film comprises polycaprolactone or polydioxanone.
[0327] Embodiment 14. The segment of embodiment 11, wherein the
polymer comprises polycaprolactone, of about 10,000 to about
150,000 Mn.
[0328] Embodiment 15. The segment of embodiment 11, wherein the
polymer film comprises polycaprolactone of about 80,000 Mn to about
110,000 Mn.
[0329] Embodiment 16. The segment of embodiment 11, wherein the
polymer film comprises polycaprolactone of about 90,000 Mn.
[0330] Embodiment 17. The segment of embodiment 11, wherein the
polymer film comprises polycaprolactone having intrinsic viscosity
of about 1.5 dL/g to about 2.1 dL/g.
[0331] Embodiment 18. The segment of any one of embodiments 1-17,
wherein polymer film further comprises a porogen.
[0332] Embodiment 19. The segment of any one of embodiments 1-17,
wherein the porogen comprises a water-soluble polymer, a
water-soluble small molecule, an inorganic salt, or an organic
salt.
[0333] Embodiment 20. The segment of any one of embodiments 1-17,
wherein the porogen comprises about 1% to about 30% by weight of
the film.
[0334] Embodiment 21. The segment of any one of embodiments 1-17,
wherein the porogen is selected from the group consisting of alkali
metal salts, sodium chloride, sodium bromide, potassium chloride,
potassium sulfate, potassium phosphate, sodium benzoate, sodium
acetate, sodium citrate, potassium nitrate, alkaline earth metal
salts, calcium chloride, calcium nitrate, transition metal salts,
ferric chloride, ferrous sulfate, zinc sulfate, cupric chloride,
saccharides, sugars, such as sucrose, glucose, fructose, mannose,
galactose, aldohexose, altrose, talose, lactose, cellulose,
monosaccharides, disaccharides, water soluble polysaccharides,
sorbitol, mannitol, organic aliphatic and aromatic oils, dials and
polyols, polyhydric alcohols, poly(alkylene glycols), polyglycols,
alkylene glycols, poly(a,m)alkylenediol esters, alkylene glycols,
poly vinylalcohol, poly vinyl pyrrolidone, water soluble polymeric
materials, Poloxamer, hypromellose Kolliphor RH40 polyvinyl
caprolactam, polyvinyl acetate (PVAc), polyethylene glycol (PEG)
Soluplus (copolymer of polyvinyl caprolactam, polyvinyl acetate,
and polyethylene glycol), copovidone, Eudragits (E, RS, RL),
poly(methyl vinyl ether-alt-maleic anhydride), polyoxyethylene
alkyl ethers, polysorbates, polyoxyethylene stearates,
polydextrose, polyacrylic acid, alginates, sodium starch glycolate,
crosslinked polyacrylic acid (carbopol), crosslinked PVP
(crospovidone), crosslinked cellulose (croscarmellose), calcium
silicate, xanthan gum, and gellan gum.
[0335] Embodiment 22. The segment of any one of embodiments 1-17,
wherein the porogen is selected from the group consisting of
povidone, copovidone, and polyoxyl castor oil.
[0336] Embodiment 23. A segment of a gastric residence system, the
segment comprising: a carrier polymer; an agent or a salt thereof;
a release-rate modulating polymer film, wherein the polymer film
comprises one or more polyester materials.
[0337] Embodiment 24. The segment of embodiment 23, wherein the
polymer film comprises polyester with a repeating unit of the
form:
--R.sup.1--O--C(.dbd.O)--
wherein R.sup.1 is selected from the group consisting of
C.sub.1-C.sub.12 alkylene groups, ethers containing between two and
twelve carbon atoms, and polyethers containing between three and
twelve carbon atoms.
[0338] Embodiment 25. The segment of embodiment 23, wherein the
polymer film comprises polycaprolactone or polydioxanone.
[0339] Embodiment 26. The segment of embodiment 23, wherein the
polymer film comprises polycaprolactone of about 10,000 to about
150,000 Mn.
[0340] Embodiment 27. The segment of embodiment 23, wherein the
polymer film comprises polycaprolactone of about 80,000 Mn to about
110,000 Mn.
[0341] Embodiment 28. The segment of embodiment 23, wherein the
polymer film comprises polycaprolactone of about 90,000 Mn.
[0342] Embodiment 29. The segment of embodiment 23, wherein the
polymer film comprises polycaprolactone having intrinsic viscosity
of about 1.5 dL/g to about 2.1 dL/g.
[0343] Embodiment 30. A segment of a gastric residence system, the
segment comprising: a carrier polymer; an agent or a salt thereof;
a release-rate modulating polymer film, wherein the polymer film
comprises a material selected from the group consisting of
polycaprolactone, cellulose acetate, and ethyl cellulose.
[0344] Embodiment 31. A segment of a gastric residence system, the
segment comprising: a carrier polymer; an agent or a salt thereof;
and a release-rate modulating polymer film, wherein the polymer
film comprises about 0.1% to about 10% of the total weight of the
segment.
[0345] Embodiment 32. The segment of embodiment 31, wherein the
polymer film comprises about 0.1% to about 5% of the total weight
of the segment.
[0346] Embodiment 33. The segment of embodiment 31, wherein the
polymer film comprises about 0.5% to about 5% of the total weight
of the segment.
[0347] Embodiment 34. The segment of embodiment 31, wherein the
polymer comprises about 0.5% to about 2% of the total weight of the
segment.
[0348] Embodiment 35. The segment of embodiment 31, wherein the
polymer film comprises about 1% to about 2% of the total weight of
the segment.
[0349] Embodiment 36. A segment of a gastric residence system, the
segment comprising: a carrier polymer; an agent or a salt thereof;
and a release-rate modulating polymer film, wherein the polymer
film has a thickness between about 1 micron and about 20
microns.
[0350] Embodiment 37. The segment of embodiment 36, wherein the
polymer has a thickness between about 5 microns and about 15
microns.
[0351] Embodiment 38. The segment of any one of embodiments 31-37,
wherein the polymer film comprises polyester with a repeating unit
of the form:
--R.sup.1--O--C(.dbd.O)--
wherein R.sup.1 is selected from the group consisting of
C.sub.1-C.sub.12 alkylene groups, ethers containing between two and
twelve carbon atoms, and polyethers containing between three and
twelve carbon atoms.
[0352] Embodiment 39. The segment of any one of embodiments 31-37,
wherein the polymer film comprises polycaprolactone or
polydioxanone.
[0353] Embodiment 40. The segment of any one of embodiments 31-37,
wherein the polymer film comprises polycaprolactone of about 10,000
to about 150,000 Mn.
[0354] Embodiment 41. The segment of any one of embodiments 31-37,
wherein the polymer film comprises polycaprolactone of about 80,000
Mn to about 110,000 Mn.
[0355] Embodiment 42. The segment of any one of embodiments 31-37,
wherein the polymer film comprises polycaprolactone of about 90,000
Mn.
[0356] Embodiment 43. The segment of any one of embodiments 31-37,
wherein the polymer film comprises polycaprolactone having
intrinsic viscosity of about 1.5 dL/g to about 2.1 dL/g.
[0357] Embodiment 44. A segment of a gastric residence system, the
segment comprising: a carrier polymer; an agent or a salt thereof;
and a release-rate modulating polymer film, wherein the polymer
film further comprises a porogen.
[0358] Embodiment 45. The segment of embodiment 44, wherein the
porogen comprises a water-soluble polymer, a water-soluble small
molecule, an inorganic salt, or an organic salt.
[0359] Embodiment 46. The segment of embodiment 44 or embodiment
45, wherein the porogen comprises about 1% to about 30% by weight
of the film.
[0360] Embodiment 47. The segment of any one of embodiments 44-46,
wherein the porogen is selected from the group consisting of alkali
metal salts, sodium chloride, sodium bromide, potassium chloride,
potassium sulfate, potassium phosphate, sodium benzoate, sodium
acetate, sodium citrate, potassium nitrate, alkaline earth metal
salts, calcium chloride, calcium nitrate, transition metal salts,
ferric chloride, ferrous sulfate, zinc sulfate, cupric chloride,
saccharides, sugars, such as sucrose, glucose, fructose, mannose,
galactose, aldohexose, altrose, talose, lactose, cellulose,
monosaccharides, disaccharides, water soluble polysaccharides,
sorbitol, mannitol, organic aliphatic and aromatic oils, diols and
polyols, polyhydric alcohols, poly(alkylene glycols), polyglycols,
alkylene glycols, poly(a,m)alkenediol esters, alkylene glycols,
poly vinylalcohol, poly vinyl pyrrolidone, water soluble polymeric
materials, Poloxamer, hypromellose (HPMC), Kolliphor RH40,
polyvinyl caprolactam, polyvinyl acetate (PVAc), polyethylene
glycol (PEG) Soluplus (copolymer of polyvinyl caprolactam,
polyvinyl acetate, and polyethylene glycol), copovidone, Eudragits
(E, RS, RL), poly(methyl vinyl ether-alt-maleic anhydride),
polyoxyethylene alkyl ethers, polysorbates, polyoxyethylene
stearates, polydextrose, polyacrylic acid, alginates, sodium starch
glycolate, crosslinked polyacrylic acid (carbopol), crosslinked PVP
(crospovidone), crosslinked cellulose (croscarmellose), calcium
silicate, xanthan gum, and gellan gum.
[0361] Embodiment 48. The segment of any one of embodiments 44-46,
wherein the porogen is selected from the group consisting of
povidone, copovidone, and polyoxyl castor oil.
[0362] Embodiment 49. The segment of any one of embodiments 44-48,
wherein the polymer film further comprises a plasticizer.
[0363] Embodiment 50. The segment of embodiment 49, wherein the
plasticizer comprises about 1% to 40% by weight of the film.
[0364] Embodiment 51. The segment of embodiment 49 or embodiment
50, wherein the plasticizer is selected from the group consisting
of phthalates, phosphates, citrates, tartrates, adipates,
sebacates, sulfonamides, succinates, glycolates, glycerolates,
benzoates, myristates, halogenated phenyls, triacetin, triethyl
citrate, PEG, and poloxamer.
[0365] Embodiment 52. The segment of embodiment 49 or embodiment
50, wherein the plasticizer is selected from the group consisting
of triethyl citrate and triacetin.
[0366] Embodiment 53. The segment of any one of embodiments 44-52,
wherein the polymer film comprises polyester with a repeating unit
of the form:
--R.sup.1--O--C(.dbd.O)--
wherein R.sup.1 is selected from the group consisting of
C.sub.1-C.sub.12 alkylene groups, ethers containing between two and
twelve carbon atoms, and polyethers containing between three and
twelve carbon atoms.
[0367] Embodiment 54. The segment of any one of embodiments 44-52,
wherein the polymer film comprises polycaprolactone or
polydioxanone.
[0368] Embodiment 55. The segment of any one of embodiments 44-52,
wherein the polymer film comprises polycaprolactone of about 10,000
to about 150,000 Mn.
[0369] Embodiment 56. The segment of any one of embodiments 44-52,
wherein the polymer film comprises polycaprolactone of about 80,000
Mn to about 110,000 Mn.
[0370] Embodiment 57. The segment of any one of embodiments 44-52,
wherein the polymer film comprises polycaprolactone of about 90,000
Mn.
[0371] Embodiment 58. The segment of any one of embodiments 44-52,
wherein the polymer film comprises polycaprolactone having
intrinsic viscosity of about 1.5 dL/g to about 2.1 dL/g.
[0372] Embodiment 59. A segment of a gastric residence system, the
segment comprising: a carrier polymer; an agent or a salt thereof;
and a release-rate modulating polymer film, wherein the polymer
film further comprises a permeable component which is permeable to
the agent or salt thereof and permeable to water.
[0373] Embodiment 60. The segment of embodiment 59, wherein the
permeable component is a polymer or a swellable material.
[0374] Embodiment 61. The segment of embodiment 59 or embodiment
60, wherein the permeable component comprises about 1% to about 30%
by weight of the film,
[0375] Embodiment 62. The segment of any one of embodiments 59-61,
wherein the permeable component is selected from the group
consisting of SSG, crospovidone, croscarmellose, and Carbopol
(PAA).
[0376] Embodiment 63. The segment of any one of embodiments 59-62,
wherein the polymer film further comprises a plasticizer.
[0377] Embodiment 64. The segment of embodiment 63, wherein the
plasticizer comprises about 1% to 40% by weight of the film.
[0378] Embodiment 65. The segment of embodiment 63 or embodiment
64, wherein the plasticizer is selected from the group consisting
of phthalates, phosphates, citrates, tartrates, adipates,
sebacates, sulfonamides, succinates, glycolates, glycerolates,
benzoates, myristates, halogenated phenyls, triacetin, triethyl
citrate, PEG, poloxamer, tributyl citrate, and dibutyl
sebacate.
[0379] Embodiment 66. The segment of embodiment 63 or embodiment
64, wherein the plasticizer is selected from the group consisting
of triethyl citrate and triacetin.
[0380] Embodiment 67. The segment of any one of embodiments 59-66,
wherein the polymer film comprises polyester with a repeating unit
of the form:
--R.sup.1--O--C(.dbd.O)--
wherein R.sup.1 is selected from the group consisting of
C.sub.1-C.sub.12 alkylene groups, ethers containing between two and
twelve carbon atoms, and polyethers containing between three and
twelve carbon atoms.
[0381] Embodiment 68. The segment of any one of embodiments 59-66,
wherein the polymer film comprises polycaprolactone or
polydioxanone.
[0382] Embodiment 69. The segment of any one of embodiments 59-66,
wherein the polymer film comprises polycaprolactone of about 10,000
to about 150,000 Mn.
[0383] Embodiment 70. The segment of any one of embodiments 59-66,
wherein the polymer film comprises polycaprolactone of about 80,000
Mn to about 110,000 Mn.
[0384] Embodiment 71. The segment of any one of embodiments 59-66,
wherein the polymer film comprises polycaprolactone of about 90,000
Mn.
[0385] Embodiment 72. The segment of any one of embodiments 59-66,
wherein the polymer film comprises polycaprolactone having
intrinsic viscosity of about 1.5 dL/g to about 2.1 dL/g.
[0386] Embodiment 73. A gastric residence system for administration
to a patient, comprising: an elastomer component, and at least
three elongate members attached to the elastomer component, wherein
each elongate member comprises a proximal end, a distal end, and an
outer surface therebetween, the proximal end of each elongate
member is attached to the elastomer component and projects radially
from the elastomer component, each elongate member has its distal
end not attached to the elastomer component and located at a larger
radial distance from the elastomer component than the proximal end;
wherein at least one elongate member comprises a segment of any one
of embodiments 1-72.
[0387] Embodiment 74. A gastric residence system for administration
to a patient, comprising at least one segment of any one of
embodiments 1-72.
[0388] Embodiment 75. A method of making a segment of a gastric
residence system comprising: coating a segment comprising a carrier
polymer and an agent or a salt thereof with a solution of a polymer
film formulation to produce a film-coated segment; and drying the
film-coated segment.
[0389] Embodiment 76. The method of embodiment 75, wherein the
coating is performed by dip coating.
[0390] Embodiment 77. The method of embodiment 75, wherein the
coating is performed by pan coating.
[0391] Embodiment 78. The method of embodiment 75, wherein the
coating is performed by spray coating.
[0392] Embodiment 79. The method of embodiment 75, wherein the
coating is performed by fluidized bed coating.
[0393] Embodiment 80. The method of any one of embodiments 75-79,
wherein the solvent used in the solution of polymer film
formulation comprises an organic solvent.
[0394] Embodiment 81. The method of embodiment 80, wherein the
solvent used in the polymer film formulation comprises ethyl
acetate, dichloromethane, acetone, isopropyl alcohol, or any
combination thereof.
[0395] Embodiment 82. A method of making a segment of a gastric
residence system comprising: co-extruding a polymer film and a
mixture of a carrier polymer and an agent or a salt thereof.
[0396] Embodiment 83. The method of any one of embodiments 75-82,
wherein the polymer film formulation comprises polyester with a
repeating unit of the form:
--R.sup.1--O--C(.dbd.O)--
wherein R.sup.1 is selected from the group consisting of
C.sub.1-C.sub.12 alkylene groups, ethers containing between two and
twelve carbon atoms, and polyethers containing between three and
twelve carbon atoms.
[0397] Embodiment 84. The method of any one of embodiments 75-82,
wherein the polymer film formulation comprises polycaprolactone or
polydioxanone.
[0398] Embodiment 85. The method of any one of embodiments 75-82,
wherein the polymer film formulation comprises polycaprolactone of
about 10,000 to about 150,000 Mn.
[0399] Embodiment 86. The method of any one of embodiments 75-82,
wherein the polymer film formulation comprises polycaprolactone of
about 80,000 Mn to about 110,000 Mn.
[0400] Embodiment 87. The method of any one of embodiments 75-82,
wherein the polymer film formulation comprises polycaprolactone of
about 90,000 Mn.
[0401] Embodiment 88. The method of any one of embodiments 75-82,
wherein the polymer film formulation comprises polycaprolactone
having intrinsic viscosity of about 1.5 dL/g to about 2.1 dL/g.
[0402] Embodiment 89. The method of any one of embodiments 75-88,
wherein polymer film further comprises a porogen.
[0403] Embodiment 90. The method of any one of embodiments 75-88,
wherein the porogen comprises a water-soluble polymer, a
water-soluble small molecule, an inorganic salt, or an organic
salt.
[0404] Embodiment 91. The method of any one of embodiments 75-88,
wherein the porogen comprises about 1% to about 30% by weight of
the film.
[0405] Embodiment 92. The method of any one of embodiments 75-88,
wherein the porogen is selected from the group consisting of alkali
metal salts, sodium chloride, sodium bromide, potassium chloride,
potassium sulfate, potassium phosphate, sodium benzoate, sodium
acetate, sodium citrate, potassium nitrate, alkaline earth metal
salts, calcium chloride, calcium nitrate, transition metal salts,
ferric chloride, ferrous sulfate, zinc sulfate, cupric chloride,
saccharides, sugars, such as sucrose, glucose, fructose, mannose,
galactose, aldohexose, altrose, talose, lactose, cellulose,
monosaccharides, disaccharides, water soluble polysaccharides,
sorbitol, mannitol, organic aliphatic and aromatic oils, diols and
polyols, polyhydric alcohols, poly(alkylene glycols), polyglycols,
alkylene glycols, poly(a,m)alkylenediol esters, alkylene glycols,
poly vinylalcohol, poly vinyl pyrrolidone, water soluble polymeric
materials, Poloxamer, hypromellose (HPMC), Kolliphor RH40,
polyvinyl caprolactam, polyvinyl acetate (PVAc), polyethylene
glycol (PEG), Soluplus (copolymer of polyvinyl caprolactam,
polyvinyl acetate, and polyethylene glycol), copovidone, Eudragits
(E, RS, RL), poly(methyl vinyl ether-alt-maleic anhydride),
polyoxyethylene alkyl ethers, polysorbates, polyoxyethylene
stearates, polydextrose, polacrylic acid, alginates, sodium starch
glycolate, crosslinked polyacrylic acid (carbopol), crosslinked PVP
(crospovidone), crosslinked cellulose (croscarmellose), calcium
silicate, xanthan gum, and gellan gum.
[0406] Embodiment 93. The method of any one of embodiments 75-88,
wherein the porogen is selected from the group consisting of
povidone, copovidone, and polyoxyl castor oil.
[0407] Embodiment 94. The gastric residence system of embodiment
73, wherein the central elastomer is formed from liquid silicone
rubber.
[0408] Embodiment 95. The gastric residence system of embodiment 73
or embodiment 94, wherein the elongate members are attached to the
central elastomer via a disintegrating matrix.
[0409] Embodiment 96. The gastric residence system of embodiment
95, wherein the disintegrating matrix comprises HPMC-AS and
polycaprolactone.
[0410] Embodiment 97. A method of administering a gastric residence
system to a patient, comprising: administering a container
containing a gastric residence system of any one of embodiments 73,
74, or 94-96 in a compacted state to a patient, wherein the
container enters the stomach of the patient and dissolves after
entry into the stomach, releasing the gastric residence system
which then adopts its uncompacted state.
[0411] Embodiment 98. The method of embodiment 97, wherein the
patient is a human.
[0412] Embodiment 99. The method of embodiment 97 or 98, wherein
the container containing the gastric residence system is
administered by swallowing, by feeding tube, or by gastrostomy
tube.
[0413] Embodiment 100. The segment of any one of embodiments 1-72,
the gastric residence system of any one of embodiments 73, 74, 94,
95, or 96, or the method of any one of embodiments 75-93 or 97-99,
wherein the agent or salt thereof is not an adamantane-class drug
or salt of an adamantane-class drug.
[0414] Embodiment 101. A gastric residence system comprising; a
therapeutically effective amount of an agent or a pharmaceutically
acceptable salt thereof, wherein: the gastric residence system has
a compacted configuration and an uncompacted configuration,
[0415] the gastric residence system comprises a plurality of
elongate members affixed to a central elastomer, wherein at least
one elongate member comprises: a carrier polymer, the agent or the
pharmaceutically acceptable salt thereof, and a release-rate
modulating polymer film coated on the surface of the at least one
elongate member; wherein the gastric residence system is configured
to release the agent or the pharmaceutically acceptable salt
thereof over a specified gastric residence period.
[0416] Embodiment 102. The gastric residence system of embodiment
101, wherein the agent is not an adamantane-class agent or
pharmaceutically acceptable salt of an adamantane-class agent.
[0417] Embodiment 103. The gastric residence system of embodiment
101 or embodiment 102, wherein the elongate members are affixed to
the central elastomer via linkers, wherein the linkers are
configured to weaken or degrade to allow passage of the gastric
residence system through the pylorus after the specified gastric
residence period.
[0418] Embodiment 104. The gastric residence system of embodiment
101 or embodiment 102, wherein at least one elongate member
comprises at least two segments joined by linkers, wherein the
linkers arc configured to weaken or degrade to allow passage of the
gastric residence system through the pylorus after the specified
gastric residence period.
[0419] Embodiment 105. The gastric residence system according to
any one of embodiments 101-104, wherein the release-rate modulating
polymer film comprises one or more polyester materials.
[0420] Embodiment 106. The gastric residence system of embodiment
105, wherein the polymer film comprises polyester with a repeating
unit of the form:
--R.sup.1--O--C(.dbd.O)--
wherein R.sup.1 is selected from the group consisting of
C.sub.1-C.sub.12 alkylene groups, ethers containing between two and
twelve carbon atoms, and polyethers containing between three and
twelve carbon atoms.
[0421] Embodiment 107. The gastric residence system of embodiment
106, wherein the polymer film comprises polycaprolactone or
polydioxanone.
[0422] Embodiment 108. The gastric residence system of embodiment
107, wherein the polymer film comprises polycaprolactone of about
10,000 to about 150,000 Mn.
[0423] Embodiment 109. The gastric residence system of embodiment
107, wherein the polymer film comprises polycaprolactone of about
80,000 Mn to about 110,000 Mn.
[0424] Embodiment 110. The gastric residence system of embodiment
107, wherein the polymer film comprises polycaprolactone of about
90,000 Mn.
[0425] Embodiment 111. The gastric residence system of embodiment
107, wherein the polymer film comprises polycaprolactone having
intrinsic viscosity of about 1.5 dL/g to about 2.1 dL/g.
[0426] Embodiment 112. The gastric residence system of any one of
embodiments 101-111, wherein the polymer film further comprises a
porogen.
[0427] Embodiment 113. The gastric residence system of embodiment
112, wherein the porogen comprises a water-soluble polymer, a
water-soluble small molecule, an inorganic salt, or an organic
salt.
[0428] Embodiment 114. The gastric residence system of embodiment
112 or embodiment 113, wherein the porogen comprises about 5% to
about 30% by weight of the film.
[0429] Embodiment 115. The gastric residence system of any one of
embodiments 112-114, wherein the porogen is selected from the group
consisting of alkali metal salts, sodium chloride, sodium bromide,
potassium chloride, potassium sulfate, potassium phosphate, sodium
benzoate, sodium acetate, sodium citrate, potassium nitrate,
alkaline earth metal salts, calcium chloride, calcium nitrate,
transition metal salts, ferric chloride, ferrous sulfate, zinc
sulfate, cupric chloride, saccharides, sugars, such as sucrose,
glucose, fructose, mannose, galactose, aldohexose, altrose, talose,
lactose, cellulose, monosaccharides, disaccharides, water soluble
polysaccharides, sorbitol, mannitol, organic aliphatic and aromatic
oils, diols and polyols, polyhydric alcohols, poly(alkylene
glycols), polyglycols, alkylene glycols, poly(a,m)alkylenediol
esters, alkylene glycols, poly vinylalcohol, poly vinyl
pyrrolidone, water soluble polymeric materials, Poloxamer,
hypromellose (HPMC), Kolliphor RH40, polyvinyl caprolactam,
polyvinyl acetate (PVAc), polyethylene glycol (PEG), Soluplus
(copolymer of polyvinyl caprolactam, polyvinyl acetate, and
polyethylene glycol), copovidone, Eudragits (E, RS, RL),
poly(methyl vinyl ether-alt-maleic anhydride), polyoxyethylene
alkyl ethers, polysorbates, polyoxyethylene stearates,
polydextrose, polyacrylic acid, alginates, sodium starch glycolate,
crosslinked polyacrylic acid (carbopol), crosslinked PVP
(crospovidone), crosslinked cellulose (croscarmellose), calcium
silicate, xanthan gum, and gellan gum.
[0430] Embodiment 116. The gastric residence system of any one of
embodiments 112-114, wherein the porogen is selected from the group
consisting of povidone, copovidone, and polyoxyl castor oil.
[0431] Embodiment 117. The gastric residence system of any one of
embodiments 101-116, wherein the polymer film further comprises a
plasticizer.
[0432] Embodiment 118. The gastric residence system of embodiment
117, wherein the plasticizer comprises triethyl citrate, triacetin,
PEG, poloxamer, tributyl citrate, or dibutyl sebacate.
[0433] Embodiment 119. The gastric residence system of embodiment
117 or embodiment 118, wherein the plasticizer comprises about 5%
to about 30% by weight of the film.
[0434] Embodiment 120. The gastric residence system of any one of
embodiments 101-119, wherein the polymer film further comprises an
anti-tack agent.
[0435] Embodiment 121. The gastric residence system of embodiment
120, wherein the anti-tack agent is selected from the group
consisting of magnesium stearate, talc, and glycerol
monostearate.
[0436] Embodiment 122. The gastric residence system of any one of
embodiments 101-121, wherein the carrier polymer comprises a
polylactone.
[0437] Embodiment 123. The gastric residence system of embodiment
122, wherein the polylactone comprises polycaprolactone.
[0438] Embodiment 124. The gastric residence system of embodiment
123, wherein the polycaprolactone has an average M.sub.n of about
60,000 to about 100,000.
[0439] Embodiment 125. The gastric residence system of embodiment
123, wherein the polycaprolactone has an average M.sub.n of about
75,000 to about 85,000.
[0440] Embodiment 126. The gastric residence system of embodiment
123, wherein the polycaprolactone has an average M.sub.n of about
80,000.
[0441] Embodiment 127. The gastric residence system of any one of
embodiments 101-126, wherein the elongate members further comprise
at least one excipient.
[0442] Embodiment 128. The gastric residence system of embodiment
127, wherein the at least one excipient comprises a polyalkylene
glycol.
[0443] Embodiment 129. The gastric residence system of embodiment
128, wherein the polyalkylene glycol is selected from the group
consisting of polyethylene glycol (PEG), polypropylene glycol
(PPG), and a block copolymer of PEG and PPG.
[0444] Embodiment 130. The gastric residence system of embodiment
128, wherein the polyalkylene glycol comprises a block copolymer of
PEG and PPG.
[0445] Embodiment 131. The gastric residence system of embodiment
130, wherein the block copolymer of PEG and PPG comprises
H--(OCH.sub.2CH.sub.2).sub.x--(O--CH(CH.sub.3)CH.sub.2).sub.y--(OCH.sub.2-
CH.sub.2).sub.z--OH, where x and z are about 101 and v is about
56.
[0446] Embodiment 132. The gastric residence system of any one of
embodiments 101-131, wherein the elongate members further comprise
an anti-oxidant.
[0447] Embodiment 133. The gastric residence system of any one of
embodiments 101-132, wherein the elongate members further comprise
silica.
[0448] Embodiment 134. The gastric residence system of any one of
embodiments 101-133, wherein the central elastomer comprises
silicone rubber. Embodiment 135. The gastric residence system of
any one of embodiments 101-134, wherein the plurality of elongate
members comprises at least three elongate members.
[0449] Embodiment 136. The gastric residence system of any one of
embodiments 101-134, wherein the plurality of elongate members is
six elongate members.
[0450] Embodiment 137. The gastric residence system of any one of
embodiments 101-136, wherein the system has a gastric residence
period of about four days to about eight days when administered to
a human patient.
[0451] Embodiment 138. The gastric residence system of any one of
embodiments 101-136, wherein the system has a gastric residence
period of about seven days to about ten days when administered to a
human patient.
[0452] Embodiment 139. The gastric residence system of any one of
embodiments 101-138, wherein the system is configured to have a
dissolution profile characterized by about 10% to 20% dissolution
of the initial amount of the agent or pharmaceutically acceptable
salt thereof present in the system during an initial 24 hour period
in an aqueous environment.
[0453] Embodiment 140. The gastric residence system of any one of
embodiments 101-138, wherein the system is configured to have a
dissolution profile characterized by about 20% to 40% dissolution
of the initial amount of the agent or pharmaceutically acceptable
salt thereof present in the system during an initial 48 hour period
in an aqueous environment.
[0454] Embodiment 141. The gastric residence system of embodiment
139 or embodiment 140, wherein the aqueous environment is the
stomach of a mammal.
[0455] Embodiment 142. The gastric residence system of embodiment
139 or embodiment 140, wherein the aqueous environment is the
stomach of a human patient.
[0456] Embodiment 143. The gastric residence system of embodiment
139 or embodiment 140, wherein the aqueous environment is simulated
gastric fluid, fasted state simulated gastric fluid, or fed state
simulated gastric fluid.
[0457] Embodiment 144. The gastric residence system of any one of
embodiments 101-143, wherein the system comprises between about 10
mg to about 400 mg of agent or pharmaceutically acceptable salt
thereof
[0458] Embodiment 145. A gastric residence system comprising: a
carrier polymer;
[0459] an agent or a salt thereof; and a release-rate modulating
polymer film configured to control the release rate of the agent or
salt thereof; wherein over a seven-day incubation of the system in
simulated gastric fluid, the amount of the agent or salt thereof
released from the system during day 5 is at least about 40% of the
amount of agent or salt thereof released during day 2; and wherein
at least about 7% of the total amount of agent or salt thereof in
the system is released on day 2 and at least about 7% of the total
amount of agent or salt thereof is released on day 5.
[0460] Embodiment 146. A gastric residence system comprising: a
carrier polymer; an agent or a salt thereof; and a release-rate
modulating polymer film configured to control the release rate of
the agent or salt thereof, wherein over a seven-day incubation of
the system in simulated gastric fluid, the amount of the agent or
salt thereof released from the system during day 7 is at least
about 20% of the amount of agent or salt thereof released during
day 1; and wherein at least about 4% of the total amount of agent
or salt thereof in the system is released on day 1 and at least
about 4% of the total amount of agent or salt thereof is released
on day 7.
[0461] Embodiment 147. A gastric residence system comprising: a
carrier polymer, an agent or a salt thereof; and a release-rate
modulating polymer film configured to control the release rate of
the agent or salt thereof; wherein the release-rate modulating
polymer film is configured such that the release of agent or salt
thereof from the system in 40% ethanol/60% simulated gastric fluid
over one hour is no more than about 40% higher compared to release
of agent or salt thereof from an equivalent system in 100%
simulated gastric fluid over one hour.
[0462] Embodiment 148. A gastric residence system comprising: a
carrier polymer, an agent or a salt thereof; and a release-rate
modulating polymer film configured to control the release rate of
the agent or salt thereof, wherein the release-rate modulating
polymer film is configured such that the release of agent or salt
thereof from the system in 40% ethanol/60% simulated gastric fluid
over one hour is at least about 40% lower than the release of agent
or salt thereof from a second system in 40% ethanol/60% simulated
gastric fluid over one hour, the second system comprising the same
combination of carrier polymer and agent or salt thereof but
lacking the release-rate modulating polymer film.
[0463] Embodiment 149. A gastric residence system comprising: a
carrier polymer, an agent or a salt thereof; and a release-rate
modulating polymer film configured to control the release rate of
the agent or salt thereof, wherein the release-rate modulating
polymer film is configured such that the release of agent or salt
thereof from the system in simulated gastric fluid over an initial
6 hour period is at least about 40% lower than the release of agent
or salt thereof from a second system in simulated gastric fluid
over an initial 6 hour period, the second system comprising the
same combination of carrier polymer and agent or salt thereof but
lacking the release-rate modulating polymer film; and wherein the
release of agent or salt thereof from the system in simulated
gastric fluid over a seven-day period is at least about 60% of the
total amount of agent or salt thereof originally present in the
system.
[0464] Embodiment 150. The gastric residence system of embodiment
149, wherein the release of agent or salt thereof from the system
in simulated gastric fluid over a seven-day period is at least
about 70% of the release of the total amount of agent or salt
thereof originally present in the system.
[0465] Embodiment 151. The gastric residence system of embodiment
149, wherein the release of agent or salt thereof from the system
in simulated gastric fluid over a seven-day period is at least
about 80% of the release of the total amount of agent or salt
thereof originally present in the system.
[0466] Embodiment 152. A gastric residence system comprising: a
carrier polymer; an agent or a salt thereof; and a release-rate
modulating polymer film, wherein the polymer film is configured to
control the release rate of the agent or salt thereof such that a
best-fit linear regression model of the release rate of agent or
salt thereof from the system in simulated gastric fluid has a
coefficient of determination R.sup.2 of at least about 0.8 over an
initial period of seven days; and wherein the system releases about
40% to about 60% of the agent or salt thereof within a time of
about 40% to about 60% of the seven-day period.
[0467] Embodiment 153. A gastric residence system providing an
extended release agent dosage form, comprising: a plurality of
elongate members comprising a therapeutically effective amount of
an agent or a pharmaceutically acceptable salt thereof and a
carrier polymer, wherein the agent or pharmaceutically acceptable
salt thereof is blended with the carrier polymer such that the
agent or salt thereof is distributed throughout the elongate
member, and a release-rate modulating polymer film coating at least
one elongate member; wherein the plurality of elongate members are
attached to a central elastomer; and wherein said gastric residence
system provides extended release of the agent or pharmaceutically
acceptable salt thereof.
[0468] Embodiment 154. The gastric residence system of embodiment
153, wherein the elongate members further comprise one or more
additional component selected from the group consisting of an
excipient and an anti-oxidant, wherein the one or more additional
component is blended together with the agent or pharmaceutically
acceptable salt thereof and the carrier polymer, such that the
agent or salt thereof and one or more additional components are
distributed throughout the elongate member.
[0469] Embodiment 155. The gastric residence system of embodiment
153 or embodiment 154, wherein the carrier polymer is blended with
the agent or pharmaceutically acceptable salt thereof and the one
or more additional component if present, by melting and mixing
together the carrier polymer, the agent or pharmaceutically
acceptable salt thereof, and the one or more additional component
if present.
[0470] Embodiment 156. The gastric residence system of any one of
embodiments 153-155, wherein the elongate members are attached to
the central elastomer via linkers, wherein the linkers are
configured to weaken or degrade to allow passage of the gastric
residence system through the pylorus after the specified gastric
residence period.
[0471] Embodiment 157. The gastric residence system of any one of
embodiments 153-155, wherein at least one elongate member comprises
at least two segments joined by linkers, wherein the linkers are
configured to weaken or degrade to allow passage of the gastric
residence system through the pylorus after the specified gastric
residence period.
[0472] Embodiment 158. The gastric residence system of embodiment
156, wherein the release-rate modulating polymer film is coated
onto the elongate member by coating the elongate member with a
solution of a polymer film formulation to produce a film-coated
elongate member; and drying the film-coated elongate member.
[0473] Embodiment 159. The gastric residence system of embodiment
157, wherein the release-rate modulating polymer film is coated
onto the segments by coating the segments with a solution of a
polymer film formulation to produce a film-coated segment; and
drying the film-coated segment.
[0474] Embodiment 160. The gastric residence system of embodiment
158 or embodiment 159, wherein the coating is performed by dip
coating.
[0475] Embodiment 161. The gastric residence system of embodiment
158 or embodiment 159, wherein the coating is performed by pan
coating.
[0476] Embodiment 162. The gastric residence system of embodiment
158 or embodiment 159, wherein the coating is performed by spray
coating.
[0477] Embodiment 163. The gastric residence system of embodiment
158 or embodiment 159, wherein the coating is performed by
fluidized bed coating.
[0478] Embodiment 164. The gastric residence system of any one of
embodiments 158-163, wherein the solvent used in the solution of
polymer film formulation comprises an organic solvent.
[0479] Embodiment 165. The gastric residence system of embodiment
164, wherein the solvent used in the polymer film formulation
comprises ethyl acetate, dichloromethane, acetone, isopropyl
alcohol, or any combination thereof.
[0480] Embodiment 166. A segment of a gastric residence system
coated with a release-rate modulating polymer film or an elongate
member of a gastric residence system coated with a release-rate
modulating polymer film, prepared by co-extruding a polymer film
and a mixture of a carrier polymer and an agent or a
pharmaceutically acceptable salt thereof to form the segment or
elongate member.
[0481] Embodiment 167. A method of making a segment of a gastric
residence system coated with a release-rate modulating polymer film
or an elongate member of a gastric residence system coated with a
release-rate modulating polymer film, comprising: co-extruding a
polymer film and a mixture of a carrier polymer and an agent or a
pharmaceutically acceptable salt thereof to form the segment or
elongate member.
[0482] Embodiment 168. A method of making a gastric residence
system, comprising: blending an agent comprising an agent or a
pharmaceutically acceptable salt thereof with a carrier polymer to
form a carrier polymer-agent blend or a carrier polymer-agent salt
blend, such that the agent or salt thereof is distributed
throughout the carrier polymer-agent blend or the carrier
polymer-agent salt blend; forming a plurality of elongate members
from the carrier polymer-agent blend or the carrier polymer-agent
salt blend, wherein the agent or salt thereof is distributed
throughout the elongate member; coating the plurality of elongate
members with a release-rate modulating polymer film; and attaching
the plurality of elongate members to a central elastomer.
[0483] Embodiment 169. The method of embodiment 168, wherein at
least one elongate member comprises at least two segments joined by
linkers, wherein the linkers are configured such that they no
longer join the at least two segments of each elongate member after
the specified gastric residence period.
[0484] Embodiment 170. A method of making a gastric residence
system, comprising: blending an agent comprising an agent or a
pharmaceutically acceptable salt thereof with a carrier polymer to
form a carrier polymer-agent blend or a carrier polymer-agent salt
blend, such that the agent or salt thereof is distributed
throughout the carrier polymer-agent blend or the carrier
polymer-agent salt blend; forming a plurality of segments from the
carrier polymer-agent blend or the carrier polymer-agent salt
blend, wherein the agent or salt thereof is distributed throughout
the segments; coating the segments with a release-rate modulating
polymer film; forming a plurality of elongate members by joining at
least two segments together via a linker to make the elongate
members; and attaching the plurality of elongate members to a
central elastomer.
[0485] Embodiment 171. The method of any one of embodiments
168-170, further comprising blending one or more additional
component selected from the group consisting of an excipient and an
anti-oxidant with the agent or pharmaceutically acceptable salt
thereof and the carrier polymer, such that the agent or salt
thereof and one or more additional components are distributed
throughout the carrier polymer-agent blend or the carrier
polymer-agent salt blend.
[0486] Embodiment 172. The method of any one of embodiments
168-171, wherein the blending of the agent or pharmaceutically
acceptable salt thereof and the one or more additional components
if present, comprises melting and mixing together the carrier
polymer, the agent or pharmaceutically acceptable salt thereof, and
the one or more additional component if present.
[0487] Embodiment 173. The method of any one of embodiments
168-172, wherein the elongate members are attached to the central
elastomer via linkers, wherein the linkers are configured such that
they no longer join the elongate members to the central elastomer
after a specified gastric residence period.
[0488] Embodiment 174. The method of any one of embodiments
168-173, wherein the coating of the release-rate modulating polymer
film onto the elongate members or the segments comprises: coating
the elongate members or segments with a solution of a polymer film
formulation to produce a film-coated elongate member or a
film-coated segment; and drying the film-coated elongate member or
film-coated segment.
[0489] Embodiment 175. The method of any one of embodiments
168-174, wherein the coating comprises dip coating.
[0490] Embodiment 176. The method of any one of embodiments
168-174. wherein the coating comprises pan coating.
[0491] Embodiment 177. The method of any one of embodiments
168-174, wherein the coating comprises spray coating.
[0492] Embodiment 178. The method of any one of embodiments
168-174, wherein the coating comprises fluidized bed coating.
[0493] Embodiment 179. The method of any one of embodiments
174-178, wherein the solvent used in the solution of polymer film
formulation comprises an organic solvent.
[0494] Embodiment 180. The method of embodiment 179, wherein the
solvent used in the polymer film formulation comprises ethyl
acetate, dichloromethane, acetone, isopropyl alcohol, or any
combination thereof.
[0495] Embodiment 181. A gastric residence system, made by any of
the methods of embodiments 168-180.
[0496] Embodiment 182. A method of making a segment of a gastric
residence system coated with a release-rate modulating polymer film
or an elongate member of a gastric residence system coated with a
release-rate modulating polymer film, comprising,: co-extruding a
polymer film and a mixture of a carrier polymer and an agent or a
pharmaceutically acceptable salt thereof to form the segment or
elongate member.
[0497] Embodiment 183. A gastric residence system providing an
extended release agent dosage form, comprising a therapeutically
effective amount of an agent or a pharmaceutically acceptable salt
thereof and a release rate-modulating polymer film adapted to
provide extended release of the agent or salt thereof in an aqueous
environment, wherein the system has a dissolution profile
characterized by about 10% to 20% dissolution of the initial amount
of agent present in the system during an initial 24 hour period in
the aqueous environment.
[0498] Embodiment 184. The gastric residence system of embodiment
183, wherein the system has a dissolution profile characterized by
about 20% to 40% dissolution of the initial amount of agent present
in the system during an initial 48 hour period in the aqueous
environment.
[0499] Embodiment 185. The gastric residence system of embodiment
183 or embodiment 184, wherein the aqueous environment is the
stomach of a human patient.
[0500] Embodiment 186. The gastric residence system of embodiment
183 or embodiment 184, wherein the aqueous environment is simulated
gastric fluid.
[0501] Embodiment 187. The gastric residence system of any one of
embodiments 183-186, wherein the system has a gastric residence
period of at least about four days when administered to a human
patient.
[0502] Embodiment 188. The gastric residence system of embodiment
187, wherein the system has a gastric residence period of at about
seven days.
[0503] Embodiment 189. The gastric residence system of any one of
embodiments 183-188, wherein the agent or pharmaceutically
acceptable salt thereof is blended with the component adapted to
provide extended release of the agent or salt thereof
[0504] Embodiment 190. The gastric residence system of embodiment
189, wherein the gastric residence system further comprises a
carrier polymer and at least one excipient, and the agent or a
pharmaceutically acceptable salt thereof and the at least one
excipient are dispersed within the carrier polymer.
[0505] Embodiment 191. A segment of a gastric residence system, the
segment comprising: a carrier polymer; an agent or a salt thereof;
and a release-rate modulating polymer film configured to control
the release rate of the agent or salt thereof, wherein over a
seven-day incubation of the segment in simulated gastric fluid, the
amount of the agent or salt thereof released from the segment
during day 5 is at least about 40% of the amount of agent or salt
thereof released during day 2; and wherein at least about 7% of the
total amount of agent or salt thereof in the segment is released on
day 2 and at least about 7% of the total amount of agent or salt
thereof is released on day 5.
[0506] Embodiment 192. A gastric residence system providing an
extended release agent dosage form, comprising: a plurality of
elongate members, wherein at least one elongate member comprises a
therapeutically effective amount of an agent or a pharmaceutically
acceptable salt thereof and a carrier polymer, and wherein the
agent or pharmaceutically acceptable salt thereof is blended with
the carrier polymer such that the agent or salt thereof is
distributed throughout the at least one elongate member; wherein
the agent or pharmaceutically acceptable salt thereof comprises
about 40% to about 60% by weight of the at least one elongate
member; wherein the plurality of elongate members are attached to a
central elastomer; and wherein said gastric residence system
provides extended release of the agent or pharmaceutically
acceptable salt thereof.
[0507] Embodiment 193. A gastric residence system providing an
extended release agent dosage form, comprising: a plurality of
elongate members, wherein at least one elongate member comprises a
therapeutically effective amount of an agent or a pharmaceutically
acceptable salt thereof and a carrier polymer, wherein the agent or
pharmaceutically acceptable salt thereof is blended with the
carrier polymer such that the agent or salt thereof is distributed
throughout the at least one elongate member, and a release-rate
modulating polymer film coating the at least one elongate member;
wherein the agent or pharmaceutically acceptable salt thereof
comprises about 40% to about 60% by weight of the at least one
elongate member; wherein the plurality of elongate members are
attached to a central elastomer; and wherein said gastric residence
system provides extended release of the agent or pharmaceutically
acceptable salt thereof.
[0508] Embodiment 194. The gastric residence system of any one of
embodiments 101-144, 152-165, 181, 183-190, 192 or 193, or the
segment of embodiment 166 or embodiment 191, wherein the agent or
pharmaceutically acceptable salt thereof comprises about 40% to
about 60% by weight of the at least one elongate member of
embodiments 101-144, 152-165, 181, 183-190, 192 or 193 or about 40%
to about 60% by weight of the segment of embodiment 166 or
embodiment 191, excluding the weight of any elastomer or linker
attached to the at least one elongate member or the segment.
[0509] Embodiment 195. The gastric residence system of any one of
embodiments 101-144, 152-165, 181, 183-190, 192 or 193, or the
segment of embodiment 166 or embodiment 191, wherein the agent or
pharmaceutically acceptable salt thereof comprises about 51% to
about 60% by weight of the at least one elongate member of
embodiments 101-144, 152-165, 181, 183-190, 192 or 193 or about 51%
to about 60% by weight of the segment of embodiment 166 or
embodiment 191.
[0510] Embodiment 196. The gastric residence system of any one of
embodiments 145-152, wherein the agent or pharmaceutically
acceptable salt thereof is present in an amount by weight of
between about 67% and about 150% of the weight of the carrier
polymer.
[0511] Embodiment 197. The gastric residence system of any one of
embodiments 73, 74, 94, 95, 96, 101-165, 181, 183-190, 192 or 193,
or the segment of any one of embodiments 1-72, 166, or 191, or the
method of any one of embodiments 75-93, 97-99, 167-180, or 182,
wherein the agent or pharmaceutically acceptable salt thereof
comprises donepezil or a salt thereof.
[0512] Embodiment 198. The gastric residence system of any one of
embodiments 73, 74, 94, 95, 96, 101-165, 181, 183-190, 192 or 193,
or the segment of any one of embodiments 1-72, 166, or 191, or the
method of any one of embodiments 75-93, 97-99, 167-180, or 182,
wherein the agent or pharmaceutically acceptable salt thereof
comprises doxycycline or a salt thereof.
[0513] Embodiment 199. The gastric residence system of any one of
embodiments 73, 74, 94, 95, 96, 101-165, 181, 183-190, 192 or 193,
or the segment of any one of embodiments 1-72, 166, or 191, or the
method of any one of embodiments 75-93, 97-99, 167-180, or 182,
wherein the agent or pharmaceutically acceptable salt thereof
comprises between about 10% to about 40% by weight of the elongate
members or segment.
[0514] Embodiment 200. The gastric residence system of any one of
embodiments 73, 74, 94, 95, 96, 101-165, 181, 183-190, 192 or 193,
or the segment of any one of embodiments 1-72, 166, or 191, or the
method of any one of embodiments 75-93, 97-99, 167-180, or 182,
wherein the agent or pharmaceutically acceptable salt thereof
comprises between about 40% to about 60% by weight of the elongate
members or segment.
EXAMPLES
[0515] The invention is further illustrated by the following
non-limiting examples.
Example 1
Drug Release From Monolithic Matrix Formulations Slows Over
Time
[0516] Monolithic polymer matrix formulations were tested for their
drug release rate over time. As can be seen from FIG. 2A,
representative monolithic polymer matrix formulations of memantine
hydrochloride showed tapering release rates over time (see Table 1
below). All formulations contained 0.5% w/w silica, 0.5% w/w alpha
tocopherol, drug content and excipients listed below, and the
balance 80 k polycaprolactone (PCL). M17: 20% w/w memantine, 7%
Eudragit E, 2% P407; M18: 20% w/w memantine, 25% Eudragit RS, 5%
P407; M27: 20% w/w memantine, 10% Eudragit RS, 5% P407; M48: 35%
w/w memantine, 2% Poloxamer P188. This slowing over time drug
release manner for monolithic polymer matrix formulations is
consistent with the Higuchi model for matrix-based drug release. In
the Higuchi model, cumulative release is proportional to the square
root of time and the proportionality constant depends on the
properties of the matrix (porosity, tortuosity) and drug solubility
(Dash et al, Acta Poloniae Pharmaceutica--Drug Research, Vol. 67
No. 3 pp. 217n223, 2010). A linear relationship between time and
the square of cumulative release was observed for a wide range of
drug-polymer blends studied, with representatives shown in FIG. 2B.
While drug release from the matrix could be accelerated or
decelerated by varying the properties of the polymer matrix, in
each case the release rate slowed significantly over time. In the
monolithic matrix systems studied, the dose of drug delivered on
day 1 was typically four- to six-fold greater than the dose
delivered on day 7. While this tapering dose profile may be
acceptable for certain applications, a more linear release profile
is desired for many indications. The linearity versus extent of
release for about 50 formulations of memantine hydrochloride
studied is shown in FIG. 2C. Total release over 7 days (X-value in
Table 1) is plotted versus the ratio of (Day 7 Release/Day 1
Release) (Y-value in Table 1) in FIG. 2C. Formulations closer to
the upper right corner of the plot (where good total release and
good linearity of release occur) are preferable. As can be seen
from FIG. 2C, drug release on day 7 was typically 10-30% of release
on day 1. Linearity of release, as measured by the ratio of release
on day 7 to release on day 1, correlated negatively with total
release at 7 days. Thus, in developing matrix-based systems,
achieving complete release in a 7-day treatment time requires
sacrificing linearity of release, which is consistent with the
Higuchi model.
Example 2A
Dip Coated Polycaprolactone Provides Superior Ethanol
Resistance
[0517] Cellulose acetate (CA), ethyl cellulose (EC), copolymers of
acrylate and methacrylate esters (e.g., Eudragit RS) and
polycaprolactone (PCL) were tested as release rate-modulating
polymer films.
Formulation Preparation
[0518] Memantine hydrochloride was blended with PCL and other
excipients on a Haake MiniCTW micro-compounder. The components were
batch mixed at 100-120.degree. C. for 10 min and then extruded into
2-mm cylinders. The molten extrudate was pressed into a compression
mold in the shape of a 20-mm rod of triangular cross section and
allowed to cool at room temperature.
[0519] Representative formulations are listed in Table 1.
TABLE-US-00008 TABLE 1 Representative formulations of memantine.
Formulation Memantine 80K PCL Y- X- Code (% ww) (% ww) Excipient (%
ww) value value M1 20 70 9% EPO, 0.5% Silica, 0.5%
.alpha.-tocopherol 0.16 59.35 M2 20 70 9% P407, 0.5% Silica, 0.5%
.alpha.-tocopherol 0.18 23.36 M3 20 70 4.5% EPO, 4.5% P407, 0.5%
Silica, 0.5% .alpha.-tocopherol 0.16 25.48 M4 20 70 9% Poly Vinyl
Acetate, 0.5% Silica, 0.5% .alpha.-tocopherol 0.14 4.87 M5 20 70 9%
PVP, 0.5% Silica, 0.5% .alpha.-tocopherol 0.18 13.47 M6 20 70 9%
Kollidon VA64, 0.5% Silica, 0.5% .alpha.-tocopherol 0.08 28.63 M7
20 74 5% Kolliphor RH40, 0.5% Silica, 0.5% .alpha.-tocopherol 0.09
9.41 M16 20 70 9% EPO, 0.5% Silica, 0.5% .alpha.-tocopherol 0.19
33.77 M17 20 70 7% EPO, 2% P407, 0.5% Silica, 0.5%
.alpha.-tocopherol 0.20 37.33 M18 20 49 25% Eudragit RS, 5% P407,
0.5% Silica, 0.5% .alpha.-tocopherol 0.11 89.73 M19 20 74 5% SIF,
0.5% Silica, 0.5% .alpha.-tocopherol 0.12 9.81 M20 20 70 9% SIF.
0.5% Silica, 0.5% .alpha.-tocopherol 0.22 28.97 M21 20 49 25%
Eudragit RL, 5% P407, 0.5% Silica, 0.5% .alpha.-tocopherol 0.00
91.57 M22 20 49 30% PDO, 0.5% Silica, 0.5% .alpha.-tocopherol 0.00
20.04 M23 20 70 9% EPO, 0.5% Silica, 0.5% .alpha.-tocopherol 0.17
50.17 M24 20 57 20% Eudragit RS, 2% P407, 0.5% Silica, 0.5%
.alpha.-tocopherol 0.17 57.73 M25 20 59.2 19.8% Eudragit RS, 0.5%
Silica, 0.5% .alpha.-tocopherol 0.31 21.61 M26 20 56.5 17.5%
Eudragit RS, 5% P407, 0.5% Silica, 0.5% .alpha.-tocopherol 0.18
70.45 M27 20 64 10% Eudragit RS, 5% P407, 0.5% Silica, 0.5%
.alpha.-tocopherol 0.15 78.20 M28 20 64 14.78% Eudragit RS, 0.226%
P407, 0.5% Silica, 0.5% .alpha.-tocopherol 0.22 16.08 M29 20 54 25%
Eudragit RS, 0.5% Silica, 0.5% .alpha.-tocopherol 0.28 30.93 M30 20
55.25 21.25% Eudragit RS, 2.5% P407, 0.5% Silica, 0.5%
.alpha.-tocopherol 0.23 45.59 M31 20 49 25% Eudragit RS, 5% P407,
0.5% Silica, 0.5% .alpha.-tocopherol 0.10 79.42 M32 14.37 56.63
39.5% PEG-PCL, 0.36% Silica, 0.36% .alpha.-tocopherol 0.00 6.27 M33
20 62.5 10% Eudragit RS, 5% P407, 2% Silica, 0.5%
.alpha.-tocopherol 0.13 68.62 M34 20 65 10% Eudragit RS, 2.5% P407,
2% Silica, 0.5% .alpha.-tocopherol 0.23 22.65 M35 20 69 3.5%
Eudragit RS, 5% P407, 2% Silica, 0.5% .alpha.-tocopherol 0.17 35.89
M36 20 71.5 3.5% Eudragit RS, 2.5% P407, 2% Silica, 0.5%
.alpha.-tocopherol 0.12 11.14 M37 22.5 64.5 6.75% Eudragit RS,
3.75% P407, 2% Silica, 0.5% .alpha.-tocopherol 0.20 49.37 M38 25
57.5 10% Eudragit RS, 5% P407, 2% Silica, 0.5% .alpha.-tocopherol
0.12 74.11 M39 25 64 3.5% Eudragit RS, 5% P407, 2% Silica, 0.5%
.alpha.-tocopherol 0.13 77.66 M40 25 66.5 3.5% Eudragit RS, 2.5%
P407, 2% Silica, 0.5% .alpha.-tocopherol 0.19 20.43 M41 20 64 10%
Eudragit RS, 5% P407, 0.5% Silica, 0.5% .alpha.-tocopherol 0.17
65.14 M42 35 64 0.5% Silica, 0.5% .alpha.-tocopherol 0.12 7.40 M43
35 62 2% P407, 0.5% Silica, 0.5% .alpha.-tocopherol 0.17 47.96 M44
35 62 0.5% Silica, 2% P407, 0.5% .alpha.-tocopherol 0.13 70.22 M45
35 62 0.5% Silica, 2% P407, 0.5% .alpha.-tocopherol 0.15 39.91 M46
35 62 0.5% Silica, 2% P407, 0.5% .alpha.-tocopherol 0.14 55.38 M47
35 62 0.5% Silica, 2% P407, 0.5% .alpha.-tocopherol 0.15 43.59 M48
35 62 0.5% Silica, 2% P407, 0.5% .alpha.-tocopherol 0.16 57.47 M49
35 59 0.5% Silica, 3% Eudragit RS, 2% P407, 0.5% .alpha.-tocopherol
0.08 86.84 M50 35 60 0.5% Silica, 2% P188, 2% P407, 0.5%
.alpha.-tocopherol 0.09 87.84 M51 40 57 0.5% Silica, 2% P407, 0.5%
.alpha.-tocopherol 0.05 91.39 M52 40 59 0.5% Silica, 0.5%
.alpha.-tocopherol 0.14 14.08 M53 45 52 0.5% Silica, 2% P407, 0.5%
.alpha.-tocopherol 0.00 86.72 M54 45 54 0.5% Silica, 0.5%
.alpha.-tocopherol 0.11 79.42 M55 50 47 0.5% Silica, 2% P407, 0.5%
.alpha.-tocopherol 0.00 85.24 M56 50 49 0.5% Silica, 0.5%
.alpha.-tocopherol 0.00 90.63 M57 20 62 12% Eudragit RL, 5%
Kolliphor P407, 0.5% Silica, 0.5% .alpha.-tocopherol 0.01 85.77 M58
20 62 6% Eudragit RL, 6% Eudragit RS, 5% Kolliphor P407, 0.5% 0.05
88.40 Silica, 0.5% .alpha.-tocopherol M59 20 62 9% Eudragit RL, 3%
Eudragit RS, 5% Kolliphor P407, 0.5% 0.01 87.95 Silica, 0.5%
.alpha.-tocopherol M60 20 62 3% Eudragit RL, 9% Eudragit RS, 5%
Kolliphor P407, 0.5% 0.08 88.63 Silica, 0.5% .alpha.-tocopherol M62
20 68 6% Eudragit RL, 5% Kolliphor P407, 0.5% Silica, 0.5%
.alpha.-tocopherol 0.00 86.67 M77 27.5 66.5 5% Kolliphor P407, 0.5%
Silica, 0.5% .alpha.-tocopherol 1.42 91.30 M104 40 58 1% Kolliphor
P407, 0.5% Silica, 0.5% .alpha.-tocopherol 0.01 103.8 M107 45 52 2%
Kolliphor P407, 0.5% Silica, 0.5% .alpha.-tocopherol 0.00 94.8
Dip Coating
[0520] Coating solutions were prepared by dissolving coating
components into appropriate organic solvents. Compositions of
coating solutions used in ethanol release studies are shown in FIG.
3A. Drug arms were gripped with forceps, completely submerged in
the coating solution, and immediately removed. Coated arms were
dried in a fume hood overnight.
In Vitro Release
[0521] Fasted state simulated gastric fluid (FaSSGF) was prepared
per the manufacturer's instructions (www.biorelevant.com).
Individual coated drug arms were incubated in 10 mL release media
in a shaking incubator at 37.degree. C. for 7 days. Drug content in
the release media was typically analyzed after 6 hours, 24 hours,
and then daily for up to 7 days by HPLC. At each time point, the
entire volume of release media was replaced with fresh media. For
ethanol release studies, drug arm were incubated in 40% ethanol in
FaSSGF for the first hour of the study. After one hour, the release
media was sampled for analysis and the ethanolic release media was
replaced with FaSSGF for the remainder of the 7-day study.
Coating Stability to Ethanol
[0522] Drug arms were prepared as above and contained 20% w/w
memantine hydrochloride, 0.5% silica, 0.5% alpha tocopherol, 25%
Eudragit RS, 5% P407, and balance 80 k PCL. Arms were coated by dip
coating using the coating solutions described in FIG. 3A. Memantine
release from coated drug arms was evaluated over 7 days in FaSSGF
as well as 1 hour in 40% ethanol in FaSSGF followed by the
remainder of the 7 days in FaSSGF. During the 1 hour in 40%
ethanol, drug content was analyzed at IS-minute intervals. Results
are shown in FIGS. 3B-3E.
[0523] In each case, release was accelerated upon exposure to
ethanol during the first hour, Clear differences were observed
among coatings with regard to their ability to resist dose dumping
in ethanol. Ethanol soluble coatings, such as Eudragit RS, were
most susceptible to dose dumping, with a greater than five-fold
increase in drug release in 6 hours (FIG. 3B). Coatings that are
insoluble in ethanol, such as PCL, demonstrated minimal change in
drug release upon exposure to ethanol (FIG. 3C). Ethyl cellulose
(FIG. 3D) and cellulose acetate (FIG. 3E) coatings displayed
intermediate ethanol stability. After switching from ethanol to
FaSSGF, the remainder of the release profile was generally similar
to the release profile observed in FaSSGF without ethanol
exposure.
Example 2B
Pan Coated Polycaprolactone
Pan Coating
[0524] This experiment was performed to explore Ethyl Cellulose
(EC) coatings on M57 (20% w/w memantine, 62% w/w 80 k PCL, 12% w/w
Eudragit RL, 5% w/w Kolliphor P407, 0.5% w/w silica, 0.5% w/w
.alpha.-tocopherol) drug loaded arms using a pharmaceutical pan
coating process in an effort to create a dosage form with linear
release over seven days.
[0525] Solutions of EC were prepared in both 100% acetone and 80:20
acetone:isopropyl alcohol with the plasticizer triethyl citrate
(TEC) in an EC:TEC ratio of 9:1 and solid concentrations of 2.3-10%
w/v. The solution was then applied to drug loaded arms using a
Vector LDCS pharmaceutical pan coater. The coating solution was
applied to a pre-weighed bed of placebo arms with a small quantity
of drug loaded arms spiked in. The pan speed was set at 20 RPM and
the product temperature was approximately 35-40.degree. C. After
coating, the arms were dried for approximately 5 minutes to drive
off any residual acetone. The entire batch of coated placebo and
drug loaded arms were weighed to determine the percent mass gain of
coating applied. Coatings were applied to a percent mass gain of
approximately 2-7% w/w.
[0526] The resulting drug loaded arms all had coatings that were
not well adhered. The coated placebo and active arms had visual
imperfections where the coating was clearly not in contact with the
drug arm matrix. Coatings could be easily removed by scratching the
surface of the drug arm. Lack of coating adhesion was likely due to
the drug arm having a smooth surface that does not allow adequate
integration of the coating layer and surface,
Example 3
Solvent Selection for Dip Coating With PCL
[0527] This example demonstrates investigation of solvents useful
for dip coating PCL films.
[0528] Dip coating requires dissolution of coating polymers in a
volatile solvent at a concentration sufficient to leave a
continuous polymer film on a dipped material. Coating thickness,
and in turn drug release rate, can be modulated by varying the
solution concentration and/or viscosity. For 80 k PCL coatings, a
minimum solution concentration of about 3% wt/vol. was necessary to
deposit a polymer layer that provided some control over drug
release. Concentrations of 5-10% wt/vol are preferred for robust
coating performance. This requires high solubility of PCL in the
coating solvent and limits the possible solvent systems that can be
used to apply coatings. FIG. 4 summarizes solvents used for dip
coating PCL films. Dichloromethane and ethyl acetate were both able
to dissolve PCL at high concentrations and to form uniform coatings
with good performance. Ethyl acetate was chosen as the preferred
solvent over dichloromethane for operator safety during processing.
For coatings incorporating porogens, the appropriate solvent
selection criteria include dissolution of an adequate concentration
of porogen. If necessary, co-solvent systems such as ethyl
acetate/isopropanol allow addition of porogens to a PCL coating
solution.
Example 4
Coatings Comprising Porogens Achieve Linear and Complete
Release
[0529] The burst release from the uncoated drug formulation could
be controlled by coating the drug arm matrix with a 5% w/v PCL
coating solution, however, it also reduced the total drug released
in 7 days from .about.90% (uncoated) to .about.60% cumulative
release. In this experiment, the effect of adding porogens to the
5% w/v PCL coating to speed up the linear release profile and
increase the cumulative drug released in 7 days was studied.
Dissolution tests were performed for 7 days in fasted state SGF
media.
[0530] The coating process was performed by dipping the drug-loaded
M77 formulation (arms) into a coating solution. Coating solutions
of 80 k PCL were prepared in ethyl acetate at 5% w/v with 90:10 PCL
to porogens (Kollidon VA64, Kolliphor RH40 and PVP). In case of
PVP, a co-solvent system of 8:2 ethyl acetate to isopropyl alcohol
(IPA) was used. In vitro release (dissolution) assay described in
Example 2A was performed to study the effect of addition of porogen
to coating solution using various porogens.
[0531] The addition of porogen to the outer coating layer increases
the cumulative 7 day release to >80%, similar to the cumulative
7-day release of the uncoated formulation, while controlling the
burst release. Dissolution results from this study showed that a
controlled release coating with porogens allows control of the
burst release and improved linearity of release, while achieving a
high 7-day cumulative drug release (FIG. 5).
Example 5
Porogen Incorporation Improves Reproducibility of Release Kinetics
for PCL-Based Coatings
[0532] The coating process was performed by dipping the drug-loaded
formulation (arms) into coating solutions as described in Example 2
on two separate experimental runs (Run 1 and Run 2). Two coating
solutions were prepared for each run: 5% w/v 80 k PCL only in ethyl
acetate and 80 k PCL with porogen (Kollidon VA64) solution was
prepared in ethyl acetate at 5% w/v with 90:10 PCL to porogen. For
both Run 1 and 2, dissolution assays were performed by incubating
dosage forms for 7 days in FaSSGF as described in the in vitro
release method in Example 2.
[0533] Dissolution results from this study (FIG. 6) showed that
addition of porogen to the 80 k PCL coating solution helps improve
batch-to-batch reproducibility of drug release profile of Run 1 and
Run 2. The PCL only coating solution leads to variability in the
release profile of Run 1 and Run 2 (FIG. 6).
Example 6
Release Rate Can Be Tuned by Varying the Ratio of Porogens
[0534] This experiment was performed to study the effect of
changing the composition of the 80 k PCL and porogen coating on
tuning the release rate of the dosage form after dip coating.
Coating solutions of 80 k PCL and porogens were prepared at 5% w/v
with the appropriate solvent as described in Examples 3 and 4 at
two different ratios of PCL to porogens, 90:10 and 70:30. Drug arms
were dip coated and dissolution tests were performed for 7 days as
described in Example 2.
[0535] Dissolution results from this study (FIG. 7) showed that
drug arms coated with 70:30 PCL:porogen ratios have a faster
release profile than arms coated with 90:10 PCL:porogen ratios, for
various porogens tested (Kollidon VA64, Kolliphor RH40 and PVP).
Increasing the amount of porogen in the coating solution increases
the rate of drug release from the coated formulations in case of
various porogens added to the PCL coating solution (FIG. 7).
Varying the level of porogen allows tuning the release rate of the
coated dosage forms (FIG. 7).
Example 7
Linearity of Release Depends on the Type of Porogen Used in the
Coating
[0536] This experiment was performed to explore how the level of
the porogen poly(ethylene glycol) (PEG 6000) in a PCL coating
affects the release rate of the dosage unit. Coating solutions were
prepared using fixed amounts of plasticizer with varying ratios of
PCL to PEG 6000.
[0537] Solutions of PCL, PEG 6000 and TEC were prepared in ethyl
acetate at 3.3% w/v with 70:30. 80:20 and 90:10 ratios of PCL to
PEG 6000 and 30% triethyl citrate by coating material, with 2%
magnesium stearate as a processing aid. The solution was then
applied to M57 (20% w/w memantine, 62% w/w 80 k PCL, 12% w/w
Eudragit RL, 5% w/w Kolliphor P407, 0.5% w/w Silica, 0.5% w/w
.alpha.-tocopherol) drug loaded arms using a Vector LDCS
pharmaceutical pan coater. The coating solution was applied to a
pre-weighed bed of placebo arms (approximately 500 g) with a small
quantity (approximately 80 arms) of drug loaded arms spiked in. The
pan speed was set at 20-22 RPM and the product temperature was
approximately 40.degree. C. After coating the arms were dried for
approximately 5 minutes to drive off any residual ethyl acetate.
The entire batch of coated placebo and drug loaded arms were
weighed to determine the percent mass gain of coating applied. Drug
arms were coated to approximately 2.5% w/w mass gain.
[0538] Dissolution results from this study showed that
incorporating PEG 6000 into the coating does not result in a linear
release profile and does not create consistent results batch to
batch as displayed in runs 1 and 2, both coated with 80:20 PCL: PEG
6000 with 30% TEC at approximately 2.5% mass gain (FIG. 8). Phase
separation of PCL and PEG 6000 was observed during the coating
which is the likely cause of the lack of controlled release.
Example 8
Plasticizer Concentration in Coatings Can Be Used to Tune the
Release Rate (Pan Coating)
[0539] This experiment was performed to explore how the level of
the plasticizer TEC in a PCL coating affects the release rate of
the dosage unit after coating in a pharmaceutical pan coater.
Coating solutions were prepared using fixed ratios of PCL to the
porogen copovidone with varying levels of the plasticizer TEC.
[0540] Solutions of PCL and copovidone were prepared in ethyl
acetate at 3.3% w/v with a 80:20 ratio of PCL to copovidone.
Triethyl citrate was added to the solution at a level of 10 or 30%
w TEC /w polymer. Magnesium stearate (2% w/w polymer) was added as
a processing aid. The solution was then applied to M77 (27.5% w/w
memantine, 66.5% w/w 80 k PCL, 5% w/w Kolliphor P407, 0.5% w/w
Silica, 0.5% NON .alpha.-tocopherol) drug loaded arms using a
Vector LDCS pharmaceutical pan coater. The coating solution was
applied to a pre-weighed bed of placebo arms (approximately 450 g)
with a small quantity (approximately 80 arms) of drug loaded arms
spiked in. The pan speed was set at 20-22 RPM and the product
temperature was approximately 40.degree. C. After coating, the arms
were dried for approximately 5 minutes to drive off any residual
ethyl acetate. The entire hatch of coated placebo and drug loaded
arms were weighed to determine the percent mass gain of coating
applied. Drug arms were coated to approximately 1.5% and 2.5% w/w
mass gain.
[0541] The dissolution results for these arms show that release
rate can be tuned by adjusting the amount of TEC in the coating
solution (FIGS. 9A and 9B). Increased ratios of TEC to PCL results
in faster dissolution when the ratio of PCL to copovidone and
coating % mass gain are held constant.
Example 9
Release Rate Can Be Tuned by Varying the Ratio of Porogens (Pan
Coating)
[0542] This experiment was performed to explore how the level of
the porogen copovidone in a PCL coating affects the release rate of
the dosage unit after pharmaceutical pan coating. Coating solutions
were prepared using fixed amounts of plasticizer with varying
ratios of PCL to copovidone.
[0543] Solutions of PCL and copovidone were prepared in ethyl
acetate at 3.3% w/v with a 80:20 ratio of PCL to copovidone.
Triethyl citrate was added to the solution at a level of 10 or 30%
w TEC/w polymer. Magnesium stearate 2% w/w polymer) was added as a
processing aid. The solution was then applied to drug loaded arms
using a Vector LDCS pharmaceutical pan coater. The coating solution
was applied to a pre-weighed bed of placebo arms (approximately 500
g) with a small quantity (approximately 80 arms) of M77 (27.5% w/w
memantine, 66.5% w/w 80 k PCL, 5% w/w Kolliphor P407, 0.5% w/w
Silica, 0.5% w/w .alpha.-tocopherol) drug loaded arms spiked in.
The pan speed was set at 20-22 RPM and the product temperature was
approximately 40.degree. C. After coating, the arms were dried for
approximately 5 minutes to drive off any residual ethyl acetate.
The entire batch of coated placebo and drug loaded arms were
weighed to determine the percent mass gain of coating applied. Drug
arms were coated to approximately 2.5% w/w mass gain.
[0544] The dissolution results for these arms show that release
rate can be tuned by adjusting the ratio of PCL:copovidone in the
coating solution (FIGS. 10A and 10B). Increased ratios of
PCL:copovidone results in slower dissolution when the amount of TEC
and coating % mass gain is held constant.
Example 10
Coatings Applied by Pan Coating Can Control Rate of Release With
Minimal Coating Mass
[0545] This experiment was performed to explore whether low coating
weights (<2.5% w/w mass gain which gives about 6 to 12 .mu.m
coating thickness range) of PCL pan coated drug loaded arms were
able to control release rate and provide linear release for 7
days.
[0546] Solutions of PCL and copovidone were prepared in ethyl
acetate at 3.3% why with a 80:20 ratio of PCL to copovidone.
Triethyl citrate was added to the solution at a level of 10 or 30%
w TEC/w polymer. Magnesium stearate 2% w/w polymer) was added as a
processing aid. The solution was then applied to drug loaded arms
using a Vector LDCS pharmaceutical pan coater. The coating solution
was applied to a pre-weighed bed of placebo arms (approximately 500
g) with a small quantity (approximately 80 arms; approximately 10
g) of M77 (27.5% w/w memantine, 66.5% w/w 80 k PCL, 5% w/w
Kolliphor P407, 0.5% w/w silica, 0.5% w/w .alpha.-tocopherol) drug
loaded aims spiked in. The pan speed was set at 20-22 RPM and the
product temperature was approximately 40.degree. C. After coating,
the arms were dried for approximately 5 minutes to drive off any
residual ethyl acetate. The entire batch of coated placebo and drug
loaded arms were weighed to determine the percent mass gain of
coating applied. Drug arms were coated to approximately 1.5% w/w
mass gain. The dissolution data for these aims show that release
rate can controlled at coating percent mass gains of less than 2.5%
and as low as 1.5% (FIG. 11).
Example 11
Coating of Drug-Polymer Arms in Wurster Coater
[0547] Drug polymer arms can also be coated in a fluid bed using a
Wurster coating process. In this process, the drug polymer arms are
fluidized with heated air and coated with a coating solution, e.g.,
5% w/w PCL in ethyl acetate, while circulating through the Wurster
column. The dissolved coating solution is applied to the drug
polymer arms as they enter the Wurster column and pass through the
spray zone situated under the column. Solvent evaporation occurs as
the arms travel through the column and circulate hack down to the
bed of polymer drug arms. This process is continued until the
appropriate amount of coating has been applied to the drug polymer
arms. Arms are then dried by turning off the coating spray and
allowing the heat and air flow to drive off remaining solvent.
Example 12
Coated Drug Arms Lead to More Consistent Drug Serum Levels of
Memantine HCl Than Uncoated Dose Forms in the Absence of Alcohol
Challenge
[0548] Eight male beagles (n=4/group) weighing between 9.3 and 11.1
kg were used in this study. Dogs were fasted for 12 hr prior to
dose administration. Dosage forms consisted of 90A durometer
polyurethane elastomers heat welded to M57 (20% w/w memantine, 62%
w/w 80 k PCL, 12% w/w Eudragit RL, 5% w/w Kolliphor P407, 0.5% w/w
Silica, 0.5% w/w .alpha.-tocopherol) drug arms that were dip coated
with a solution of 6.67% ethyl cellulose w/v in acetone or
uncoated. Memantine was incorporated into the drug-polymer arms at
a total load of .about.155 mg/dosage form for an estimated
.about.22 mg/day of potential release over 7 days. (Formulations
for animal studies in Examples 12-14 are listed in Table 2.)
TABLE-US-00009 TABLE 2 Memantine formulations. 80K Formulation
Memantine PCL Code (% ww) (% ww) Excipient (% ww) Coating Solution
Composition M57 20 62 12% Eudragit RL, 5% Kolliphor P407, 6.67%
ethyl cellulose w/v in 0.5% Silica, 0.5% .alpha.-tocopherol acetone
M69 27.5 56.5 12% Eudragit RL, 3% Kolliphor P407, 5% PCL w/v in
ethyl acetate 0.5% Silica, 0.5% .alpha.-tocopherol M77 27.5 66.5 5%
Kolliphor P407, 0.5% Silica, 0.5% 4.5% PCL/0.5% Kollidon VA64
.alpha.-tocopherol w/v in ethyl acetate
[0549] Coated and uncoated dosage forms were placed into capsules
immediately before dosing. Capsules were placed at the back of the
dog's throat and after swallowing, dogs were offered a food chase
of canned food. Blood samples (2 mL) were collected from left or
right jugular veins pre-dose and at 2, 4, 6, 24, 48, 72, 96, 120,
144 and 168 hr after dosing. Blood samples were collected into
K.sub.3EDTA tubes and plasma collected by centrifugation at 5,000
rpm for 5 min. Plasma samples were analyzed for memantine content
using a protein precipitation method followed by quantitation on
LC-MS/MS (FIG. 12).
Example 13
PCL Coating Results in Near Constant Plasma Drug Concentrations
Despite Variations in the Underlying Formulation: Six Dog Study
[0550] Six male beagles weighing between 9.1 and 10.8 kg were used
in this study. Dogs were fasted for 12 hr prior to dose
administration. Dosage forms consisted of 90A durometer
polyurethane elastomers heat welded to M69 (27.5% w/w memantine,
56.5% w/w 80 k PCL, 12% w/w Eudragit RL, 3% w/w Kolliphor P407,
0.5% w/w Silica, 0.5% w/w .alpha.-tocopherol) drug arms that were
dip coated with a solution of 5% PCL w/v in ethyl acetate.
Memantine was incorporated into the drug-polymer arms at a total
load of .about.183 mg/dosage form for an estimated .about.26 mg/day
of potential release over 7 days. (See Table 2 above for memantine
formulations.) Coated and uncoated dosage forms were placed into
capsules immediately before dosing.
[0551] Capsules were placed at the back of the dog's throat and
after swallowing, dogs were offered a food chase of canned food.
Blood samples (2 mL) were collected from left or right jugular
veins pre-dose and at 2, 4, 6, 24, 48, 72, 96, 120, 144 and 168 hr
after dosing. Blood samples were collected into K.sub.3EDTA tubes
and plasma collected by centrifugation at 5,000 rpm for 5 min.
Plasma samples were analyzed for memantine content using a protein
precipitation method followed by quantitation on LC-MS/MS. The
results of the study are shown in FIG. 13.
Example 14
PCL Coating Results in Near Constant Plasma Drug Concentrations
Despite Variations in the Underlying Formulation: Sixteen Dog
Study
[0552] Sixteen male beagles weighing between 8.2 and 10.1 kg were
used in this study. Dogs were fasted for 12 hr prior to dose
administration, and then subjected to one of three different
feeding regimens: (food 1 hour prior to dose administration. food 1
hour after dose administration, and food 4 hours after dose
administration). Dosage forms consisted of 60A durometer LSR
elastomers IR welded to 50/50 PCL/HPMAS disintegrating matrices and
M77 (27.5% w/w memantine, 66.5% w/w 80 k PCL, 5% w/w Kolliphor
P407, 0.5% w/w Silica, 0.5% w/w .alpha.-tocopherol) drug arms that
were coated with a solution of 4.5% PCL/0.5% kollidon VA64 w/v in
ethyl acetate. Memantine was incorporated into the drug-polymer
arms at a total load of .about.145 mg/dosage form for an estimated
.about.21 mg/day of potential release over 7 days. (See Table 2
above for memantine formulations.) Coated and uncoated dosage forms
were placed into capsules immediately before dosing,
[0553] Capsules were placed at the hack of the dog's throat and
after swallowing, dogs were offered a food chase of canned food.
Blood samples (2 mL) were collected from left or right jugular
veins pre-dose and at 2, 4, 6, 8, 24, 48, 72, 96, 120, 144, 168,
192 and 240 hr after dosing. Blood samples were collected into
K.sub.3EDTA tubes and plasma collected by centrifugation at 5,000
rpm for 5 min. Plasma samples were analyzed for memantine content
using a protein precipitation method followed by quantitation un
LC-MS/MS. The results are shown in FIG. 14.
[0554] For comparison, the same animals were administered Namenda
XR containing 28 mg of memantine and plasma samples were collected
and analyzed in a similar manner. Pharmacokinetic parameters for
individual animals are shown in FIG. 16. The mean Cmax values for
the dosage form and Namenda XR were 46.1.+-.15.2 and 64.9.+-.20.7
ng/mL, respectively, and mean AUC values for the dosage form and
Namenda XR were 7438.+-.1590 and 1,113.+-.382 hr*ng/mL,
respectively. Despite the range of fed/fasted conditions, the
variability of Cmax and AUC observed with coated dosage forms was
equal or less than for Namenda XR. The relative standard deviations
(RSD) of the dosage form Cmax and AUC were 33% and 21%,
respectively, while the corresponding RSDs for Namenda XR were 32%
and 34%. In addition, the Cmax observed following dosage form
administration was lower than the value observed following the
lower dose of Namenda. XR The AUC observed following dosage form
administration was approximately 7 times higher than the Namenda
XR, AUC, indicating that the bioavailability of memantine was
similar for both formulations.
Example 15
Coating of Drug-Polymer Matrix Increases Linearity of Drug
Release
[0555] Linearity versus extent of release for about 50 formulations
of memantine hydrochloride was evaluated, in which drug-polymer
matrices were coated in accordance with the present invention in
comparison with uncoated formulations (Example 1). Total release
over 7 days (X-value in Table 3) is plotted versus the ratio of
(Day 7 Release/Day 1 Release) (Y-value in Table 3) in FIG. 15.
Formulations closer to the upper right corner of the plot (where
good total release and good linearity of release occur) are
preferable. As can be seen in FIG. 15, drug release on day 7 was up
to 100% of release on day 1. Linearity of release, as measured by
the ratio of release on day 7 to release on day 1 was greater than
30% for many formulations, including many formulations that
displayed near complete cumulative release at Day 7. In systems of
the present invention, achieving complete release in a 7-day
treatment time is possible while maintaining near linear release
(Day 7 release/Day 1 release>0.3). Coating formulations were as
listed in Table 3.
TABLE-US-00010 TABLE 3 Coating formulations. Coating Solution
Formulation Coating Concentration Y- X- Code Coating Formulation
Solvent (% w/v) value value M18 9:1, PCL 55k:P407 DCM 33.3 0.94
30.92 M18 9:1, PCL 55k:P188 DCM 33.3 0.69 49.84 M18 Eudragit RS DCM
33.3 0.15 88.68 M18 9:1 PCL 55k:PEG 10k DCM 33.3 0.95 33.73 M18 9:1
PCL 55k:PEG 100k DCM 33.3 0.91 35.34 M18 PCL 55k DCM 16.7 0.60
70.61 M18 9:1, PCL 55k:P407 DCM 16.7 0.62 54.22 M18 9:1, PCL
55k:P188 DCM 16.7 0.57 54.21 M18 9:1 PCL 55k:PVP 1M DCM 16.7 0.42
74.51 M18 Ethyl Cellulose Acetone 6.7 0.19 82.44 M18 9:1 Ethyl
Cellulose:PVP 1.3M Acetone 6.7 0.23 81.86 M18 9:1 Ethyl
Cellulose:PEG 1M Acetone 6.7 0.44 72.87 M18 9:1 Ethyl Cellulose:PEG
100k Acetone 6.7 0.28 79.19 M18 75:25 PLGA Acetone 16.7 0.54 43.48
M18 50:50 PLGA Acetone 16.7 0.49 61.98 M18 25:75 PLGA Acetone 13.9
0.28 58.86 M18 50:50 PLGA Acetone 13.9 0.13 81.72 M18 50:50 PLGA
Acetone 13.9 0.18 72.64 M18 Ethyl Cellulose Acetone 6.7 0.25 62.67
M18 Cellulose Acetate Acetone 6.7 0.11 79.50 M18 9:1 Ethyl
Cellulose:PEG 1M Acetone 6.7 0.16 72.18 M18 9:1 Cellulose
Acetate:PEG 1M Acetone 6.7 0.10 81.60 M18 Cellulose Acetate Acetone
10.0 0.16 69.48 M18 PCL 55k Acetone 20.0 0.08 86.53 M18 PCL 15k
Acetone 20.0 0.07 87.36 M18 PLGA 50:50 Ester Terminated Acetone
16.7 0.39 56.45 35-45k M18 PLGA 50:50 Acid Terminated Acetone 16.7
0.26 72.86 35-45k M18 PCL 80k Acetone 10.0 0.10 82.69 M18 PCL 80k
Ethyl Acetate 10.0 0.26 68.57 M57 Ethyl Cellulose Acetone 6.7 0.29
73.18 M57 PCL 80k Ethyl Acetate 10.0 0.49 58.76 M58 Ethyl Cellulose
Acetone 6.7 0.41 56.02 M58 PCL 80k Ethyl Acetate 10.0 0.62 39.53
M59 Ethyl Cellulose Acetone 6.7 0.38 60.50 M59 PCL 80k Ethyl
Acetate 10.0 0.44 56.53 M60 Ethyl Cellulose Acetone 6.7 0.47 56.19
M60 PCL 80k Ethyl Acetate 10.0 0.52 49.40 M57 PCL 80k Ethyl Acetate
10.0 0.48 82.11 M57 PCL 80k Ethyl Acetate 15.0 0.78 53.78 M57 9:1
PCL 80k:TEC Ethyl Acetate 15.0 0.65 60.77 M57 8:2 PCL 80k:TEC Ethyl
Acetate 15.0 0.59 68.87 M57 7:3 PCL 80k:TEC Ethyl Acetate 15.0 0.36
88.57 M57 Ethyl Cellulose Acetone 6.7 0.45 78.07 M57 Ethyl
Cellulose Cp 10 Acetone 6.7 0.21 92.28 M57 Ethyl Cellulose Cp 10
Acetone 13.3 0.21 90.63 M57 9:1 Ethyl Cellulose Cp10:TEC Acetone
13.3 0.30 89.24 M57 8:2 Ethyl Cellulose Cp10:TEC Acetone 13.3 0.30
91.88 M57 7:3 Ethyl Cellulose Cpl0:TEC Acetone 13.3 0.25 92.46 M62
PCL 80k Ethyl Acetate 10.0 0.46 79.46 M77 PCL 80k Ethyl Acetate 3.0
0.22 81.19 M77 PCL 80k Ethyl Acetate 5.0 0.47 63.90 M77 PCL 80k
Ethyl Acetate 10.0 0.58 71.51 M77 7:3 80k PCL:PVP 8:2 Ethyl 5.0
0.03 90.69 Acelate:IPA M77 9:1 PVP 8:2 Ethyl 5.0 0.23 84.89
Acetate:IPA M77 7:3 80k PCL:Kolliphor RH40 Ethyl Acetate 5.0 0.01
90.74 M77 9:1 80k PCL:Kolliphor RH40 Ethyl Acetate 5.0 0.29 82.26
M77 7:3 80k PCL:Kollidon VA64 Ethyl Acetate 5.0 0.05 89.56 M77 9:1
80k PCL:Kollidon VA64 Ethyl Acetate 5.0 0.21 86.21 M104 1.25%
weight gain of C3 (Table 5) Ethyl Acetate 3.3 0.01 100.03 M104 2.5%
weight gain of C3 (Table 5) Ethyl Acetate 3.3 0.01 101.12 M107
1.25% weight gain of C3 (Table 5) Ethyl Acetate 3.3 0.00 95.85 M107
2.5% weight gain of C3 (Table 5) Ethyl Acetate 3.3 0.00 92.99 M104
1.25% weight gain of C4 (Table 5) Ethyl Acetate 3.3 0.08 100.02
M104 2.5% weight gain of C4 (Table 5) Ethyl Acetate 3.3 0.09 92.20
M107 1.25% weight gain of C4 (Table 5) Ethyl Acetate 3.3 0.00
100.00 M107 2.5% weight gain of C4 (Table 5) Ethyl Acetate 3.3 0.01
99.96 M104 1.25% weight gain of C5 (Table 5) Ethyl Acetate 3.3 0.01
100.85 M104 2.5% weight gain of C5 (Table 5) Ethyl Acetate 3.3 0.01
99.56 M107 1.25% weight gain of C5 (Table 5) Ethyl Acetate 3.3 0.00
84.45 M107 2.5% weight gain of C5 (Table 5) Ethyl Acetate 3.3 0.00
97.68 M104 1.25% weight gain of C6 (Table 5) Ethyl Acetate 3.3 0.49
81.38 M104 2.5% weight gain of C6 (Table 5) Ethyl Acetate 3.3 0.81
54.35 M107 1.25% weight gain of C6 (Table 5) Ethyl Acetate 3.3 0.39
94.73 M107 2.5% weight gain of C6 (Table 5) Ethyl Acetate 3.3 0.80
62.42 M104 1.25% weight gain of C7 (Table 5) Ethyl Acetate 3.3 0.07
96.68 M104 2.5% weight gain of C7 (Table 5) Ethyl Acetate 3.3 0.36
100.41 M107 1.25% weight gain of C7 (Table 5) Ethyl Acetate 3.3
0.00 91.11 M107 2.5% weight gain of C7 (Table 5) Ethyl Acetate 3.3
0.21 98.27 M107 1.25% weight gain of C8 (Table 5) Ethyl Acetate 3.3
0.56 86.36 M107 2.5% weight gain of C8 (Table 5) Ethyl Acetate 3.3
0.83 46.97
[0556] cl Example 16
Memantine High Drug Loading
[0557] This experiment was performed to explore the extrusion of
high drug load memantine formulations. Memantine formulations were
extruded at 35, 40, 45 and 55% w/w API (named M103, M104, M105 and
M106 respectively). All extrusions were performed at a 500 g scale.
The formulations in Table 4 were compounded and profile extruded
using a Leistritz 18'' hot melt extruder. Each formulation was bag
blended to create a homogenous mixture. The blended powder was fed
into the extruder hopper and compounded using a feed rate of 0.5
kg/hr. The extrudate was cooled and pelletized using an in-line
cutter to make pellets of appropriate size mm) for profile
extrusion.
[0558] The pellets were then fed into the twin screw extruder and
profile extruded using a custom triangular die and a feed rate of
0.4-0.5 kg/hr. Samples of the profile extruded drug arms were taken
every 2 minutes for the first 10 minutes and one additional sample
was taken at the beginning, middle, and end of the process. Samples
for M105 and M106 were run for Memantine content analysis. The
results show reasonable uniformity with all samples having assay of
85-115% (see FIG. 17). Samples were run for dissolution in fasted
simulated gastric fluid (FaSSGF). All samples showed complete
release over 3-4 days (see FIG. 18).
TABLE-US-00011 TABLE 4 % Composition of Memantine High Drug Load
Formulations M103 M104 M105 M106 M107 Memantine HCl 35.0 40.0 45.0
55.0 45.0 Polycaprolactone 62.0 58.0 54.0 44.0 52.0 Poloxamer P407
2.0 1.0 0.0 0.0 2.0 Colloidal Silicon 0.5 0.5 0.5 0.5 0.5 Dioxide
Vitamin E 0.5 0.5 0.5 0.5 0.5 Succinate Total 100.0 100.0 100.0
100.0 100.0
Example 17
Coating of High Drug Load Memantine to Control Release Rate
[0559] This experiment was performed to explore how coatings
containing polycaprolactone, the porogen copovidone and plasticizer
triethyl citrate (TEC) can control the release rate of M103, M104,
and M105 when applied in a LCDS pan coater.
[0560] Two solutions of PCL, copovidone and triethyl citrate were
prepared in ethyl acetate at 3.3% w/v. The first coating solution
(C1) contained a 95:5 ratio of PCL to copovidone and 10% TEC by
coating material, with 2% magnesium stearate as a processing aid.
The second solution (C2) contained 80:20 ratio of PCL to copovidone
and 15% TEC by coating material, with 2% magnesium stearate as a
processing aid. The solution was then applied to drug loaded arms
using a Vector LDCS pharmaceutical pan coater. The coating solution
was applied to approximately 480 g placebo arms with approximately
5 g of M105 drug loaded arms spiked in. The pan speed was set at
20-22 RPM and the product temperature was approximately 40.degree.
C. After coating the arms were dried for approximately 5 minutes to
drive off any residual ethyl acetate. The entire batch of coated
placebo and drug loaded arms were weighed to determine the percent
mass gain of coating applied. Drug arms were coated to
approximately 2.5% and 5.0% w/w mass gain.
[0561] The process was repeated for M103 and M104. Coating
solutions C1 and C2 were prepared again and applied to a coating
pan containing approximately 465 g placebo arms with approximately
10 g of M103 and 10 g of M104 drug loaded arms spiked in.
Processing conditions were the same as in the previous
paragraph.
[0562] All coated material was run for dissolution in FaSSGF.
Results showed that the lower amounts of porogen and plasticizer in
the C1 coating solution result in relatively slower dissolution at
similar coating weights when compared to drug arms coated with the
C2 formulation. FIG. 19 shows a graph of dissolution of formulation
M103 with C1 coating, C2 coating, and uncoated; FIG. 20 shows a
graph of dissolution of formulation M104 with C1 coating, C2
coating, and uncoated; and FIG. 21 shows a graph of dissolution of
formulation M105 with C1 coating, C2 coating, and uncoated. For
both coating formulations, increased coating weight causes slower
dissolution. These dissolution experiments show that the rate of
release from all high drug load Memantine formulations tested can
be controlled with as little as 1.5% coating weight. Coated
formulations show higher linearity than the corresponding uncoated
formulation. For example, formulation M104 with C1 coating display
correlation co-efficient (R.sup.2) values of 0.89, 0.84, 0.73
respectively for coating weights of 1.5%, 2.5%, 5.1% and M104 with
C2 coating display correlation co-efficient (R.sup.2) values of
0.98, 0.98, 0.96 respectively for coating weights of 1.5%, 2.5%,
5.2% while the uncoated M104 formulation displays a correlation
co-efficient (R.sup.2) value of 0.58.
Example 18
Coating of High Drug Load Formulations to Increase Extent of
Release
[0563] This experiment was performed to increase the extent of API
release from Example 17 using polycaprolactone coatings, with
increased amounts of porogen and the plasticizer triethyl citrate
(TEC) to control the release rate of M104 and M107 when applied in
a LCDS pan coater.
[0564] Six additional solutions of PCL, copovidone and triethyl
citrate were prepared in ethyl acetate at 3.3% w/v. The first
coating solution (C3) contained a 70:30 ratio of PCL to copovidone
and 30% TEC by coating material, with 2% magnesium stearate as a
processing aid. The second solution (C4) contained 80:20 ratio of
PCL to copovidone and 30% TEC by coating material, with 2%
magnesium stearate as a processing aid. The third solution (C5)
contained 70:30 ratio of PCL to copovidone and 20% TEC by coating
material, with 2% magnesium stearate as a processing aid. The forth
solution (C6) contained 80:20 ratio of PCL to copovidone and 20%
TEC by coating material, with 2% magnesium stearate as a processing
aid. The fifth solution (C7) contained 75:25 ratio of PCL to
copovidone and 15% TEC by coating material, with 2% magnesium
stearate as a processing aid. The sixth solution (C8) contained
80:20 ratio of PCL to copovidone and 10% TEC by coating material,
with 2% magnesium stearate as a processing aid. Coating
formulations are summarized in Table 5. The solution was then
applied to drug loaded arms using a Vector LDCS pharmaceutical pan
coater. The coating solution was applied to approximately 480 g
placebo arms with approximately 5 g of M105 drug loaded arms spiked
in. The pan speed was set at 20-22 RPM and the product temperature
was approximately 40.degree. C. After coating the arms were dried
for approximately 5 minutes to drive off any residual ethyl
acetate. The entire batch of coated placebo and drug loaded arms
were weighed to determine the percent mass gain of coating applied.
Drug arms were coated to approximately 1.25% and 2.5% w/w mass
gain. For every run M104 and M107 were coated in the same
batch,
[0565] All coated material was run for dissolution in FaSSGF.
Results showed that the increased amounts of porogen and
plasticizer in the C3, C4, C5 and C7 coating solution offer
essentially no control of drug release compared to the uncoated
arms at the coating weights tested. However, coatings C6 and C8
show sustained release over seven days for both drug arm
formulations at all coating weights. Only coatings with <20%
copovidone and 20% triethyl citrate show controlled release
compared to the uncoated drug arms. FIG. 22 shows a graph of
dissolution of formulation M104 with C3 coating, C4 coating, and
uncoated. FIG. 23 shows a graph of dissolution of formulation M104
with C5 coating, C6 coating, C7 coating, and uncoated. FIG. 24
shows a graph of dissolution of formulation M107 with C3 coating,
C4 coating, C5 coating, and uncoated. FIG. 25 shows a graph of
dissolution of formulation M107 with C6 coating, C7 coating, C8
coating, and uncoated.
TABLE-US-00012 TABLE 5 % w/w Composition of Coating Formulations C1
C2 C3 C4 C5 C6 C7 C8 polycaprolactone 83.8 66.7 48.0 54.9 54.9 62.7
62.5 70.6 copovidone 4.4 16.6 20.6 13.7 23.5 15.7 20.8 17.6
Triethyl citrate 9.8 14.7 29.4 29.4 19.6 19.6 14.7 9.8 Magnesium
stearate 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 Total 100.0 100.0 100.0
100.0 100.0 100.0 100.0 100.0
Example 19
Pan Coating of Donepezil High Drug Load Formulations With PCL
[0566] This experiment was performed to demonstrate how a
polycaprolactone (PCL) coating affects the release rate of
donepezil from the dosage unit after coating in a pharmaceutical
pan coater. A solution of PCL, copovidone and triethyl citrate
(TEC) was prepared in ethyl acetate at 3.3% w/v with a 70:17:13
ratio of PCL to copovidone to TEC. The solution was applied to
drug-loaded arms containing 40% donepezil HCl (w/w) using a Vector
LDCS pharmaceutical pan coater. The coating solution was applied to
a pre-weighed bed of placebo arms (approximately 450 g) with a
small quantity (approximately 80 arms) of drug loaded arms spiked
in. The pan speed was set at 20-22 RPM and the product temperature
was approximately 40.degree. C. After coating, the arms were dried
for approximately 5 minutes to drive off any residual ethyl
acetate. The entire batch of coated placebo and drug loaded arms
were weighed to determine the percent mass gain of coating applied.
Drug arms were coated to approximately 2.5% and 5% w/w mass
gain.
[0567] Triplicate samples of 50 mg of formulated matrix, with or
without coating, were placed in 15-ml conical tubes containing 10
ml FaSSGF. Tubes were placed in an incubator shaker at 37.degree.
C., 200 rpm. 1 ml aliquots were collected at approximately 0.25, 1,
2, 3, 4, 5, 6 and 7 days. At each sampling the remaining media was
discarded and replaced with 10 ml of fresh FaSSGF. Sample aliquots
were analyzed directly on HPLC. The results are shown in FIG. 26,
and demonstrate that coating improves linearity of release of drug
from the arms.
Example 20
Dip Coating Provides Release Rate Control for Doxycycline High Drug
Load Formulations
[0568] Drug Arm Formulation Preparation: Doxycycline hyclate was
blended with PCL and other excipients on a Haake MiniCTW
micro-compounder by first adding PCL to form a bed on heated
screws, followed by the powdered active pharmaceutical ingredient
with excipients, then with the balance of required PCL. Batch
mixing was performed at 100'C at 75 rpm for 10 minutes and sample
was extruded at 20-30 rpm into 2-mm cylinders and compression
molded to obtain 18 mm or 20 mm long triangular-cross section forms
and allowed to cool and harden at room temperature. Arm
formulations used are listed in Table 6.
TABLE-US-00013 TABLE 6 Name Composition Function DX21 7% ERL + 5%
P407 Lead formulations for coating DX23 6% ERS + 6% ERL + 2% P407
Lead formulations for coating All formulations contained 25%
Doxycycline Hyclate (granulated), 0.5% SiO2, 0.5% alpha-tocopherol,
and balance 80k PCL. ERL--Eudragit RL; ERS--Eudragit RS
[0569] Dip coating: Coating solutions were prepared by weighing
excipients into a 20 mL scintillation vial, adding a magnetic stir
bar, adding solvent, capping, and vortexing, and were allowed to
stir at 25.degree. C. (EC) or 40.degree. C. (PCL) overnight until a
clear, homogenous solution had been achieved. Compositions of
coating solutions are listed in Table 7, as the percentage of
coating material (e.g., 80 k PCL) in solution in the solvent
indicated (e.g., ethyl acetate). Drug arms were gripped with
forceps, completely submerged in the coating solution, and
immediately removed. Coated arms were dried in a fume hood
overnight.
TABLE-US-00014 TABLE 7 Base Polymer Coating solution composition
Solvent 80k PCL 8% 80k PCL Ethyl acetate (Sigma) 9% 80k PCL 10% 80k
PCL 12% 80k PCL 15% 80k PCL 18% 80k PCL 10% (9:1) 80k PCL:TEC 12%
(9:1) 80k PCL:TEC Ethyl 6.67% Ethyl cellulose Cp10 Acetone
cellulose (EC) 12% Ethyl cellulose Cp10 13.34% Ethyl cellulose CP10
15% Ethyl cellulose Cp10 18% Ethyl cellulose Cp10
[0570] In Vitro Release: Each formulation was evaluated for release
in fasted state simulated gastric fluid (FaSSGF) for seven days.
Approximately 50 mg of formulated matrix, with or without coating,
was cut and placed in 15-ml conical tubes containing 10 ml FaSSGF.
Tubes were placed in an incubator shaker at 37.degree. C., 200 rpm.
1 ml aliquots were collected at approximately 0.25, 1, 2, 3, 4, 5,
6 and 7 days. At each sampling the remaining media was discarded
and replaced with 10 ml of fresh FaSSGF. Sample aliquots were
analyzed directly on HPLC.
[0571] FIG. 27 shows release curves from DX21 Doxycycline Hyclate
hot melt extrusion (HME) formulations with 80 k PCL coatings. FIG.
28 show release curves from DX21 Doxycycline Hyclate HME
formulations with ethyl cellulose coatings. FIG. 29 shows release
curves from DX23 Doxycycline Hyclate HME formulations with 80 k PCL
coatings. FIG. 30 show release curves from DX23 Doxycycline Hyclate
HME formulations with ethyl cellulose coatings.
[0572] The results show that release of doxycycline can be
modulated and controlled by use of an appropriate release-rate
modulating film, such as the highly linear release rate achieved
over 7 days by dip-coating into 15% PCL and 18% PCL solutions in
ethyl acetate, as shown in FIG. 27.
Example 21
Reduction of pH Effect on Release Due to Pan Coating of Risperidone
High Drug Load Formulations With PCL
[0573] This experiment was performed to evaluate whether a
polycaprolactone (PCL) coating affects reduces the effect of media
pH on the rate of risperidone release from the dosage unit after
coating in a pharmaceutical pan coater. Risperidone is an example
of a drug for which the solubility is significantly higher at the
more acidic end of the gastric pH range (e.g., pH 1.5) than at the
less acidic end of the gastric pH range (e.g., pH 4.8), resulting
in faster dissolution rates at the lower pH. The release rate
control imparted by PCL-based coating is shown to reduce the ratio
between percent drug released at different pHs over time.
[0574] A solution of PCL, copovidone and triethyl citrate (TEC) was
prepared in ethyl acetate at 3.3% w/v with a 68:22:10 ratio of PCL
to copovidone to TEC. The solution was applied to two different
formulations of risperidone-loaded aims containing 40% risperidone
(w/w) using a Vector LDCS pharmaceutical pan coater. Formulation 1
consisted of 40% risperidone, 10% Soluplus, 5% Kollidon CL, 5%
P407, 0.5% .alpha.-tocopherol succinate, 0.5% silica MSP, and 39%
cryomilled Purac PC17 polycaprolactone. Formulation 2 consisted of
40% risperidone, 5% dicalcium phosphate, 5% P407, 0.5%
.alpha.-tocopherol succinate, 0.5% silica MSP, and 49% cryomilled
Purac PC17 polycaprolactone. The coating solution was applied to a
pre-weighed bed of placebo arms (approximately 450 g) with a small
quantity (approximately 40 aims) of drug-loaded arms spiked in. The
pan speed was set at 20-22 RPM and the product temperature was
approximately 40.degree. C. After coating, the arms were dried for
approximately 5 minutes to drive off any residual ethyl acetate.
The entire batch of coated placebo and drug loaded arms were
weighed to determine the percent mass gain of coating applied. Drug
arms were coated to approximately 4.5% w/w mass gain.
[0575] Samples of .about.50 mg of formulated matrix, with or
without coating, were placed in 20-ml glass vials containing 10 ml
FaSSGF pH 1.5 or ammonium acetate pH 4.8. Tubes were placed in an
incubator shaker at 37.degree. C., 200 rpm. 1 ml aliquots were
collected at approximately 6 and 24 hours. At each sampling the
remaining media was discarded and replaced with 10 ml of fresh
FaSSGF or fresh ammonium acetate buffer pH 4.8. Sample aliquots
were analyzed directly on HPLC. The presence of the release-rate
modulating coating approximately halved the effect of pH on release
rate as measured at a 6 hour time point and reduced the effect of
pH on release by about 1/3 as measured at a 24 h time point. The
results are shown in Table 8, and demonstrate that coating reduces
the difference in relative dependence of rates on media pH.
TABLE-US-00015 TABLE 8 6 hour % Release 24 hour % Release Rate
Ratio Rate Ratio Formulation pH 1.5 pH 4.8 (pH 1.5/pH 4.8) pH 1.5
pH 4.8 (pH 1.5/pH 4.8) Uncoated Formulation 1 43.8 14.6 3.0 84.0
29.9 2.8 Coated Formulation 1 16.4 10.5 1.6 55.7 27.5 2.0 Uncoated
Formulation 2 42.2 15.6 2.7 81.8 33.5 2.4 Coated Formulation 2 12 9
9.4 1.4 40.8 25.1 1.6
[0576] The disclosures of all publications, patents, patent
applications and published patent applications referred to herein
by an identifying citation are hereby incorporated herein by
reference in their entirety. Web sites references using
"World-Wide-Web" at the beginning of the Uniform Resource Locator
(URL) can be accessed by replacing "World-Wide-Web" with "www."
[0577] Although the foregoing invention has been described in some
detail by way of illustration and example for purposes of clarity
of understanding, it is apparent to those skilled in the art that
certain changes and modifications will be practiced. Therefore, the
description and examples should not be construed as limiting the
scope of the invention.
* * * * *
References